Use of VEGF antagonist for treating ocular angiogenesis disorder

Abstract

To provide a pharmaceutical composition for treating or preventing non-proliferative diabetic retinopathy.SOLUTION: A pharmaceutical composition containing VEGF antagonist to be used in a method for bringing about at least 2 steps of improvement in a diabetic retinopathy seriousness scale (DRSS) in a patient who has non-proliferative diabetic retinopathy and needs the composition, where the patient is not suffered from diabetic macular edema including a central part. The method includes administering approximately 2 mg of VEGF antagonist being a VEGF receptor-based chimeric molecule containing: VEGFR1 component including a specific amino acid sequence; VEGFR2 component including a specific amino acid sequence; and multimerized component including a specific amino acid sequence, for 5 times of monthly dosage and subsequent once or more of secondary dosage by every 8 weeks to an eye of the patient by intravitreal injection. The VEGF antagonist is preferably aflibercept.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application Nos. 62 / 593,033, filed November 30, 2017; 62 / 644,425, filed March 17, 2018; and 62 / 748,782, filed October 22, 2018, each of which is incorporated by reference in its entirety.

[0002] The present invention relates to the field of therapeutic treatment of ocular disorders. More specifically, the present invention relates to the administration of VEGF antagonists to treat ocular disorders caused by or associated with angiogenesis. [Background technology]

[0003] Several eye disorders are associated with pathological angiogenesis. For example, the development of age-related macular degeneration (AMD) is associated with a process called choroidal neovascularization (CNV). Leakage from CNV results in fluid accumulation under the macula, which leads to macular edema and vision loss. Diabetic macular edema (DME) is another eye disorder with an angiogenic component. DME is the most common cause of moderate vision loss in patients with diabetes and is a common complication of diabetic retinopathy, a disease that affects the blood vessels of the retina. Clinically significant DME occurs when fluid leaks into the center of the macula, the light-sensitive part of the retina responsible for clear, direct vision. Fluid in the macula can result in severe vision loss or blindness. Yet another eye disorder associated with abnormal angiogenesis is central retinal vein occlusion (CRVO). CRVO results from a blockage of the central retinal vein, which results in a backup of blood and fluid in the retina. The retina can become ischemic, resulting in the growth of new, inappropriate blood vessels that can result in further vision loss and even more serious complications. Release of vascular endothelial growth factor (VEGF) contributes to increased vascular permeability and inappropriate new blood vessel proliferation in the eye. Therefore, inhibiting the pro-angiogenic properties of VEGF is believed to be an effective strategy for treating angiogenic eye disorders.

[0004] FDA-approved treatments for angiogenic eye disorders such as AMD and CRVO include monthly intravitreal injections of an anti-VEGF antibody called ranibizumab (Lucentis®, Genentech, Inc.).

[0005] Methods for treating ocular disorders using VEGF antagonists are described, for example, in U.S. Patent No. 5,399,433; U.S. Patent No. 5,499,446; U.S. Patent No. 5,523,663; and U.S. Patent No. 5,523,636. Nevertheless, there remains a need in the art for new dosing regimens for angiogenic ocular disorders, particularly those that allow for less frequent dosing while maintaining high levels of efficacy. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 7,303,746 [Patent Document 2] U.S. Patent No. 7,306,799 [Patent Document 3] U.S. Patent No. 7,300,563 [Patent Document 4] U.S. Patent No. 7,303,748 [Patent Document 5] US Patent Application Publication No. 2007 / 0190058 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides a method for treating angiogenic eye disorders (e.g., diabetic retinopathy, e.g., non-proliferative diabetic retinopathy). The method of the present invention comprises sequentially administering to a patient multiple doses of a VEGF antagonist over time. Specifically, the method of the present invention comprises sequentially administering to a patient a single initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist. The inventors have surprisingly discovered that beneficial therapeutic effects can be achieved in patients suffering from angiogenic eye disorders by administering to the patient a VEGF antagonist once every 8 weeks or more, particularly when such doses are preceded by about three doses administered to the patient at a frequency of about 2 to 4 weeks. Thus, according to the method of the present invention, each secondary dose of a VEGF antagonist is administered 2 to 4 weeks after the immediately preceding dose, and each tertiary dose is administered at least 8 weeks after the immediately preceding dose. An example of a dosing regimen of the present invention is shown in FIG. 1. One advantage of such a dosing regimen is that it allows for less frequent dosing (e.g., once every 8 weeks) during the majority of the treatment course (i.e., tertiary doses) compared to prior dosing regimens for angiogenic ocular disorders that require monthly dosing throughout the treatment course (see, e.g., prescribing information for Lucentis® [ranibizumab], Genentech, Inc.). [Means for solving the problem]

[0008] The methods of the invention can be used to treat any angiogenic ocular disorder including, for example, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, and the like.

[0009] The method of the present invention comprises administering any VEGF antagonist to a patient (e.g., by intravitreal injection). In one embodiment, the VEGF antagonist comprises one or more VEGF receptor-based chimeric molecule(s) (also referred to herein as "VEGF-Trap" or "VEGFT"). An exemplary VEGF antagonist used in the context of the present invention is a multimeric VEGF-binding protein comprising two or more VEGF receptor-based chimeric molecules, referred to herein as "VEGFR1R2-FcΔC1(a)" or "aflibercept".

[0010] A variety of routes of administration are contemplated for use in the methods of the invention, including, for example, topical administration or intraocular administration (eg, intravitreal administration).

[0011] Aflibercept (EYLEA™, Regeneron Pharmaceuticals, Inc.) was approved by the FDA in November 2011 for the treatment of patients with neovascular (wet) age-related macular degeneration at a recommended dose of 2 mg administered by intravitreal injection every 4 weeks for the first 3 months, followed by 2 mg administered by intravitreal injection once every 8 weeks.

[0012] The present invention provides methods for treating diabetic retinopathy of any severity level, e.g., non-proliferative diabetic retinopathy (NPDR) (e.g., moderate to severe NPDR, e.g., characterized by a Diabetic Retinopathy Severity Scale level of about 47-53, e.g., 47 or 53), in a patient in need of treatment (e.g., a human, e.g., 18 years of age or older, e.g., having type 1 or 2 diabetes), the methods comprising administering to the patient's eye (e.g., by intravitreal injection): For example, about 2 mg of a VEGF antagonist, e.g., a VEGF receptor-based chimeric molecule, comprising: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2. (i) three monthly doses, followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks after the third monthly dose (at week 16) and continuing every 16 weeks thereafter (e.g., doses given at weeks 32, 48, 64, etc.) (see, e.g., FIG. 2); or (ii) 3 or 4 or 5 monthly doses, followed by one or more secondary doses every 8 weeks, where the secondary doses begin 8 weeks after the last of the 3 or 4 or 5 monthly doses and continue with the doses given every 8 weeks thereafter. For example, in one embodiment of the present invention, the VEGF antagonist is aflibercept. In one embodiment of the present invention, the VEGF antagonist comprises VEGFR1R2-FcΔC1(a) encoded by the nucleic acid sequence of SEQ ID NO: 1. In one embodiment of the present invention, the patient is characterized by: not having diabetic macular edema; having a baseline best-corrected visual acuity (BCVA) ETDRS letter score of 69 or higher; having visual acuity characterized by a Snellen visual acuity of 20 / 40 or better; not having retinal neovascularization; not having anterior segment neovascularization (ASNV); not having vitreous hemorrhage; and / or not having tractional retinal detachment. In one embodiment of the present invention, as discussed herein, "treating" NPDR in a patient refers to resulting in at least about a 2-step improvement in the DRSS (Diabetic Retinopathy Severity Scale) from baseline (before the first VEGF antagonist administration) by, for example, 24 or 48 or 52 weeks (relative to the start of the first VEGF antagonist administration).

[0013] The present invention provides a method for treating or preventing proliferative diabetic retinopathy (PDR) in a patient (e.g., a human) in need of such treatment or prevention; or for preventing the progression of non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy, anterior segment neovascularization (ASNV), diabetic macular edema (DME) or central involving diabetic macular edema (CI-DME), wherein the patient is initially treated for non-proliferative diabetic retinopathy (e.g., the patient has type 1 or 2 diabetes; has a hemoglobin A1c of about 8.5; has an ETDRA BCVA score of about 82; has a central retinal thickness of about 247 μm; has a Diabetic Retinopathy Severity Score of 47 or 53; and / or is about 56 years of age), the method comprising administering to the patient's eye (e.g., by intravitreal injection): For example, about 2 mg of a VEGF antagonist (e.g., aflibercept) comprising: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2. (i) 3 monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 4 or 5 monthly doses, followed by one or more secondary doses every 8 weeks For example, in one embodiment of the invention, the patient is treated for at least about 24 weeks, 52 weeks, or 100 weeks, e.g., where the patient receives about 3 to about 5 injections over a 24 week period. In one embodiment of the invention, the patient is treated, e.g., for about 24 weeks or more, and experiences the following benefits: (i) at least a two-step improvement from baseline in the Diabetic Retinopathy Severity Scale (DRSS) score; (ii) at least a three-step improvement from baseline in the Diabetic Retinopathy Severity Scale (DRSS) score; (iii) an improvement in best-corrected visual acuity of at least about 1.9 letters; (iv) not experiencing a reduction in best-corrected visual acuity of more than 4 letters; (v) not developing diabetic macular edema; (vi) not developing centrally involving diabetic macular edema; (vii) not experiencing any sight-threatening complications; (viii) not develop proliferative diabetic retinopathy; (ix) do not develop anterior segment neovascularization; and / or (x) experience a reduction in central retinal thickness of about 19 μm; Accordingly, the present invention provides that a patient with non-proliferative diabetic retinopathy can achieve one or more of the following benefits by administering a VEGF antagonist according to the dosing regimen described above: (i) at least a two-step improvement from baseline in the Diabetic Retinopathy Severity Scale (DRSS) score; (ii) at least a three-step improvement from baseline in the Diabetic Retinopathy Severity Scale (DRSS) score; (iii) an improvement in best-corrected visual acuity of at least about 1.9 letters; (iv) not experiencing a reduction in best-corrected visual acuity of more than 4 letters; (v) not developing diabetic macular edema; (vi) not developing centrally involving diabetic macular edema; (vii) not experiencing any sight-threatening complications; (viii) not develop proliferative diabetic retinopathy; (ix) do not develop anterior segment neovascularization; and / or (x) experience a reduction in central retinal thickness of about 19 μm; Also provided are methods for achieving one or more of the above.

[0014] For example, the present invention provides a method for administering to a patient's eye (e.g., by intravitreal injection): For example, about 2 mg of a VEGF antagonist (e.g., aflibercept) comprising: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2. (i) 3 monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 4 or 5 monthly doses, followed by one or more secondary doses every 8 weeks The present invention provides a method for causing a reduction or preventing an increase in Diabetic Retinopathy Severity Scale (DRSS) levels of non-proliferative diabetic retinopathy in a patient (e.g., see FIG. 18 ) (e.g., to at least levels 2 or 3), comprising administering

[0015] The present invention also provides a method for treating or preventing the onset or recurrence of sight-threatening complications or blindness in a subject (e.g., a human) eye having non-proliferative diabetic retinopathy, comprising administering (e.g., by intravitreal injection) to the subject's eye (e.g., by intravitreal injection) about 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule, (i) three monthly doses, followed by one or more secondary doses every 16 weeks, with the first secondary dose starting 8 weeks (at the 16th week) after the third monthly dose, or (ii) three or four or five monthly doses, followed by one or more secondary doses every 8 weeks. Optionally, the subject's other eye is also administered the VEGF antagonist, even if it is less affected, is affected by low levels of DRSS, or is affected by another angiogenic eye disorder. For example, in one embodiment of the invention, the VEGF antagonist comprises: (i) (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2; or (ii) (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component. (iii) is aflibercept; or (iv) is conbercept.

[0016] One aspect of the present invention is Drug containers; and In the patient's eyes, Approximately 2 mg of VEGF antagonist, a VEGF receptor-based chimeric molecule (i) 3 monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 5 monthly doses followed by one or more secondary doses every 8 weeks; instructions for using the drug to treat or prevent diabetic retinopathy in a patient in need of such treatment, showing the use of the drug by administering This is a package that includes:

[0017] In another aspect of the invention, the VEGF antagonist is (i) comprises: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232 to 457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) conbercept, It is a package.

[0018] Another aspect of the invention is a package in which the instructions indicate that the drug is administered by intravitreal injection.

[0019] Another embodiment of the invention is a package in which the instructions indicate that the drug is to be administered in 3 or 5 monthly doses, followed by one or more doses every 8 weeks.

[0020] Another embodiment of the invention is a package in which the instructions indicate that the drug is to be administered in three monthly doses, followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks after the third monthly dose (at week 16).

[0021] Another embodiment of the invention is a package in which the instructions indicate that the drug is to be administered as one dose of the drug every eight weeks.

[0022] An aspect of the present invention is Drug containers; and In the patient's eyes, Approximately 2 mg of VEGF antagonist, a VEGF receptor-based chimeric molecule (i) 3 monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 5 monthly doses followed by one or more secondary doses every 8 weeks; instructions for using the drug to treat or prevent proliferative diabetic retinopathy in a patient in need of such treatment, showing the use of the drug by administering This is a package that includes:

[0023] In another aspect of the invention, the VEGF antagonist is (i) comprises: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232 to 457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) conbercept, It is a package.

[0024] Other embodiments of the present invention will become apparent from the detailed description that follows. [Brief description of the drawings]

[0025] [Figure 1]1 shows an exemplary dosing regimen of the present invention, in which a single "initial dose" of a VEGF antagonist ("VEGFT") is administered at the beginning of the treatment regimen (i.e., "week 0"), two "secondary doses" are administered at weeks 4 and 8, respectively, and at least six "tertiary doses" are administered once every eight weeks thereafter, i.e., at weeks 16, 24, 32, 40, 48, 56, etc. This VEGF antagonist dosing regimen forms part of the present invention. [Diagram 2] 2 shows a second exemplary dosing regimen of the present invention. In this regimen, three monthly doses of VEGF antagonist ("Q4wk doses") are administered at the beginning of the treatment regimen (i.e., at weeks 0, 4 and 8), followed by a single dose 8 weeks (i.e., at week 16) after the last Q4wk dose ("Q8wk dose"), followed by three or more additional doses (i.e., at weeks 32, 48, 64, etc.) administered 16 weeks after the Q8wk dose and once every 16 weeks thereafter ("Q16wk doses"). This VEGF antagonist dosing regimen forms part of the present invention. [Diagram 3] FIG. 1 shows an overview of the Phase 3, double-blind, randomized, controlled PANORAMA study design. Patients with moderate to severe NPDR received (i) sham injections ("Sham"), (ii) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks after the third monthly dose (at week 16) ("Group 1"), or (iii) five monthly doses followed by one or more secondary doses every 8 weeks ("Group 2"). [Figure 4] FIG. 1 summarizes the PANORAMA dosing schedule for groups Sham, Group 1 and Group 2. X=active injection; O=sham injection. [Diagram 5] Figure 1 shows the baseline characteristics and demographics of the PANORAMA study population in each dosing group, including Sham, Group 1, Group 2, and Groups 1 and 2 combined (all IAI). IAI = intravitreal aflibercept injection. [Figure 6]FIG. 1 describes the baseline disease characteristics of the PANORAMA study population in each dosing group, including Sham, Group 1, Group 2, and Groups 1 and 2 combined (All IAI). [Figure 7] FIG. 1 describes the number of injections received by PANORAMA subjects in each dosing group (Sham, Group 1, Group 2, and Groups 1 and 2 combined: "All IAI"). [Figure 8] FIG. 1 shows the percentage of PANORAMA patients in each dosing group (Sham, Group 1, Group 2 and all IAI (Groups 1 and 2 combined)) achieving a ≧2-step improvement from baseline on the Diabetic Retinopathy Severity Scale (DRSS). [Figure 9] FIG. 1 shows the percentage of PANORAMA patients in each dosing group (Sham, Group 1, Group 2 and all IAI (Groups 1 and 2 combined)) achieving a ≧3-step improvement from baseline on the Diabetic Retinopathy Severity Scale (DRSS). [Figure 10] FIG. 1 shows the percentage of PANORAMA patients in each dosing group (Sham, Group 1, Group 2 and all IAIs (Groups 1 and 2 combined)) who experienced vision-threatening complications (VTC; proliferative diabetic retinopathy (PDR) / anterior segment neovascularization (ASNV)) and / or central involving diabetic macular edema (CI-DME) by week 24. [Figure 11] FIG. 1 shows a summary of the mean change in best corrected visual acuity (BCVA) scores (Early Treatment Diabetic Retinopathy Study (ETDRS) letters) for each PANORAMA dosing group (Sham, Group 1, Group 2, and Groups 1 and 2 combined: "All IAI") through 24 weeks. [Figure 12] FIG. 1 shows an overview of the mean change in central retinal thickness (CRT, μm) for each PANORAMA dosing group (Sham, Group 1, Group 2 and all IAI (Groups 1 and 2 combined)) up to 24 weeks. [Figure 13]Figure 1 shows a summary of treatment-emergent adverse events (TEAEs) in the study eye in the PANORAMA groups for sham and all IAI (groups 1 and 2 combined) through week 24. FAS / SAF = full analysis set / safety analysis set [Figure 14] Figure 1 shows a summary of severe ocular treatment-emergent adverse events (TEAEs) in the study eye in the PANORAMA groups in sham and all IAI (Groups 1 and 2 combined) through Week 24. FAS / SAF = full analysis set / safety analysis set. [Figure 15] FIG. 1 shows a summary of intraocular inflammation in the study eye experienced by the PANORAMA groups in Sham and all IAI (Groups 1 and 2 combined) up to week 24. [Figure 16] FIG. 1 shows a summary of anti-platelet trialists' collaboration (APTC) events experienced by the sham and all IAI (groups 1 and 2 combined) PANORAMA arms through week 24. [Figure 17] FIG. 1 shows an overview of deaths in PANORAMA subjects up to week 24. [Figure 18] 1 is a table detailing the International Clinical Diabetic Retinopathy Disease Severity Scale (DRSS). [Figure 19] FIG. 1 shows an overview of the results of the PANORAMA clinical trial after 52 weeks - the percentage of patients in each treatment group who experienced at least a two-step improvement in the DRSS and the percentage of subjects who developed a vision-threatening complication (VTC) and / or centrally involved diabetic macular edema (CI-DME). [Figure 20] FIG. 1 shows an overview of the number of active injections given to subjects in treatment groups Sham, 2q16 (of 6) and 2q8 (of 9) through week 52. [Figure 21]Figure 16: Overview of the proportion of patients in the Sham, 2q16 and 2q8 groups with at least a 2-step improvement from baseline in the DRSS at week 52. LOCF = last observation carried forward to week 52. [Figure 22] FIG. 14 shows an overview of the percentage of subjects in each treatment group (sham, 2q16, and 2q8) with at least a 2-step improvement from baseline in DRSS at weeks 8, 12, 24, 40, and 52. [Diagram 23] FIG. 1 shows an overview of the percentage of patients in each treatment group (sham, 2q16, and 2q8) who developed vision-threatening complications (VTCs) and / or centrally involved diabetic macular edema (CI-DME) through week 52. [Figure 24] Kaplan-Meier plot of the probability of developing a sight-threatening complication over time for subjects in each treatment group (sham, 2q16 and 2q8). VTE=VEGF Trap eye VTC=sight-threatening complication. [Diagram 25] FIG. 1 shows an overview of time to onset of CI-DME for subjects in each treatment group (sham, 2q16, and 2q8). [Figure 26] FIG. 1 shows a summary of the mean change in best corrected visual acuity (ETDRS letters) for subjects in each treatment group (sham, 2q16, and 2q8) over 52 weeks. [Figure 27] FIG. 1 shows a summary of central retinal thickness (μm) for subjects in each treatment group (sham, 2q16 and 2q8) over 52 weeks. [Figure 28] FIG. 1 shows a summary of the occurrence of ocular treatment-emergent adverse events (TEAEs) experienced by subjects in each treatment group (sham, 2q16, and 2q8), treated eye, after 52 weeks. [Figure 29] FIG. 1 shows a summary of the occurrence of serious ocular treatment-emergent adverse events (TEAEs) experienced by subjects in each treatment group (sham, 2q16, and 2q8), treated eye, after 52 weeks. [Diagram 30]FIG. 1 shows a summary of the incidence of ocular inflammation experienced by subjects in each treatment group (sham, 2q16 and 2q8), treated eye, after 52 weeks. [Diagram 31] FIG. 1 shows a summary of the occurrence of Antiplatelet Clinical Trials Collaboration (APTC) events experienced in subjects in each treatment group (sham, 2q16, and 2q8), treated eyes after 52 weeks. [Diagram 32] FIG. 1 shows an overview of the proportion of patients with ≥ 3 step improvement in each treatment group (sham, 2q16 and 2q8) after 52 weeks. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present invention comprises an exceptionally effective method for preventing the progression of non-proliferative diabetic retinopathy without diabetic macular edema in patients to more advanced vision-threatening disorders such as proliferative diabetic retinopathy, diabetic macular edema and / or anterior segment neovascularization.Indeed, patients with moderate to severe non-proliferative diabetic retinopathy in the aflibercept dosing regimen of the present invention have experienced a reversal of disease progression, achieving two or more steps of improvement in DRSS level.The eye of the subject in the dosing regimen of the present invention has also experienced a reduction in the development of vision-threatening complications compared to untreated eyes.This prevention can be achieved by administering a VEGF antagonist such as aflibercept to the eye of the patient using the dosing regimen described herein.

[0027] Before the present invention is described, it is believed that the present invention is not limited to the specific methods and experimental conditions described, since such methods and conditions may vary. It is also understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs.As used herein, the term "about" means that when used with reference to a specific cited numerical value, the value may vary from the cited value by less than 1%.For example, as used herein, the phrase "about 100" includes 99 and 101 and all values ​​therebetween (for example, 99.1, 99.2, 99.3, 99.4, etc.).

[0029] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0030] The subject or patient may be a mammal, for example, a human (e.g., a human over 50, 55, 60, 65, or 70 years of age), rabbit, mouse, non-human primate, monkey, or rat. In one embodiment of the present invention, the subject or patient has previously undergone a different treatment for DR, for example, PDR (e.g., panretinal photocoagulation (laser) treatment). In one embodiment of the present invention, the previous treatment failed to adequately treat DR. In one embodiment of the present invention, the patient or subject does not suffer from DME and / or CI-DME. In one embodiment of the present invention, the subject or patient has diabetes (e.g., type 1 or type 2).

[0031] Medication Regimen The present invention relates to diabetic retinopathy of any severity level, including proliferative or non-proliferative diabetic retinopathy. The present invention provides a method for treating angiogenic eye disorders such as retinopathies (NPDR), for example, moderate NPDR or severe NPDR. The method of the present invention comprises sequentially administering multiple doses of a VEGF antagonist (e.g., aflibercept) to the eye of a subject or patient (e.g., a human, such as a human over 18 years old). In one embodiment of the present invention, the patient has diabetes (e.g., type 1 or type 2). As used herein, "sequentially administering" means that each dose of a VEGF antagonist is administered to the eye of a patient at a different time, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes a method comprising sequentially administering a single initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist to the eye of a patient.

[0032] The present invention provides a method for treating or preventing angiogenic eye disorders (e.g., NPDR) in a subject, comprising administering 3 or 4 or 5 initial monthly doses of a VEGF antagonist (e.g., aflibercept) to the eye of the subject, followed by one or more secondary doses every 8 weeks; preventing the progression of DR (e.g., NPDR) to more severe forms or complications thereof, such as PDR, ASNV, DME and / or CI-DME; causing a reduction in the DRSS of NPDR; treating or preventing the onset or recurrence of VTC or blindness.In one embodiment of the present invention, the eye affected by the disorder is administered with the antagonist, and optionally the other eye is also treated with the same or different dosing regimen, even if the eye does not show the disorder, or if a less severe form of the disorder shows up, or if another angiogenic eye disorder afflicts the other eye. Thus, the invention provides a method comprising administering (e.g., by intravitreal injection) a 0.5 or 2 mg dose of a VEGF antagonist to the eye of a subject (e.g., a human) for 3 or 4 or 5 monthly doses, followed by doses every 8 weeks counting from the end of the first 3 or 4 or 5 monthly doses. In one embodiment of the invention, the eye afflicted with the disorder is administered the antagonist, and optionally the other eye is also treated with the same or a different dosing regimen, even if the disorder is not present in that eye, or if a less severe form of the disorder is present, or if another angiogenic eye disorder afflicts the other eye. In one exemplary embodiment of the present invention, a single initial dose (e.g., 2 mg) of a VEGF antagonist is administered to the patient's eye (e.g., by intravitreal injection) on the first day of the treatment regimen (i.e., week 0), followed by two secondary doses, each administered 4 weeks after the immediately preceding dose (i.e., weeks 4 and 8), followed by at least five tertiary doses, each administered 8 weeks after the immediately preceding dose (i.e., weeks 16, 24, 32, 40 and 48). The tertiary doses continue indefinitely (at intervals of 8 weeks or more) over the course of the treatment regimen. This exemplary administration regimen is graphically depicted in FIG. 1.

[0033] The present invention provides a method of administering to a subject's eye (e.g., by intravitreal injection): (A) administering three initial monthly doses (e.g., once every four weeks or "Q4wk") of a VEGF antagonist (e.g., 2 mg); followed by (B) administering a single dose (e.g., 2 mg) of a VEGF antagonist to the subject's eye 8 weeks ("Q8wk") after the immediately preceding dose; followed by (C) Methods for treating or preventing angiogenic eye disorders (e.g., NPDR) in a subject, comprising administering to the subject's eye one or more additional (maintenance) doses (e.g., 2 mg) of a VEGF antagonist (e.g., aflibercept) 16 weeks after the immediately preceding dose and every 16 weeks thereafter ("Q16wk") (such as weeks 32, 48 and 64 counting from the start of the first monthly dose); preventing progression to more severe forms of DR (e.g., NPDR) or complications thereof, such as PDR, ASNV, DME and / or CI-DME; resulting in a reduction in the DRSS of NPDR; treating or preventing the onset or recurrence of VTC or blindness. See, e.g., FIG. 2. The methods of the present invention include (i) administering to the subject's eye one or more additional (maintenance) doses (e.g., 2 mg) of a VEGF antagonist (e.g., aflibercept) 16 weeks after the immediately preceding dose and every 16 weeks thereafter ("Q16wk") (such as weeks 32, 48 and 64 counting from the start of the first monthly dose). wherein the first secondary dose comprises administering the VEGF antagonist at a dose of 0.1 mg / kg / day starting 8 weeks (week 16) after the third monthly dose. In one embodiment of the invention, the eye afflicted with the disorder is administered the antagonist, and optionally the other eye is also treated with the same or a different dosing regimen, even if the disorder is not present in that eye, or if a less severe form of the disorder is present, or if another angiogenic eye disorder afflicts the other eye.

[0034] In an exemplary embodiment of the invention, following the initial primary dose, each secondary dose is administered 2 to 4 weeks (e.g., 2 weeks, 2 1 / 2 weeks, 3 weeks, 3 1 / 2 weeks, or 4 weeks) after the immediately preceding dose, and each tertiary dose is administered at least 8 weeks (e.g., 8 weeks, 8 1 / 2 weeks, 9 weeks, 9 1 / 2 weeks, 10 weeks, 10 1 / 2 weeks, 11 weeks, 11 1 / 2 weeks, 12 weeks, 12 1 / 2 weeks, 13 weeks, 13 1 / 2 weeks, 14 weeks, 14 1 / 2 weeks, or more) after the immediately preceding dose. Alternatively, following the secondary doses, the VEGF antagonist is administered on an as-needed / when-needed (PRN) basis based on visual and / or anatomical outcomes assessed by a physician or other certified medical practitioner.

[0035] The present invention provides a method of administering to a subject's eye (e.g., by intravitreal injection): (A) administering three initial monthly doses (e.g., once every four weeks or "Q4wk") of a VEGF antagonist (e.g., aflibercept or conbercept, e.g., 0.5 mg or 2.0 mg); followed by (B) administering one or more doses of a VEGF antagonist to the target eye three months after the immediately preceding dose (or every 12 weeks or quarterly); or Administering a VEGF antagonist to the target eye on an as-needed / when-needed (PRN) basis based on visual and / or anatomical outcomes as assessed by a physician or other qualified healthcare professional Also included are methods for treating or preventing angiogenic eye disorders (e.g., NPDR) in a subject; preventing progression to more severe forms of DR (e.g., NPDR) or complications thereof, such as PDR, ASNV, DME and / or CI-DME; resulting in a reduction in the DRSS of NPDR; treating or preventing the onset or recurrence of VTC or blindness.

[0036] The terms "initial dose", "secondary dose" and "tertiary dose" refer to the administration of VEGF antagonists sequential in time. Thus, "initial dose" refers to the dose administered at the beginning of a treatment regimen (also referred to as "baseline dose"); "secondary dose" refers to the dose administered after the initial dose; and "tertiary dose" refers to the dose administered after the secondary dose. The initial, secondary and tertiary doses may all contain the same amount of VEGF antagonist, but generally differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of VEGF antagonist contained in the initial, secondary and / or tertiary doses varies from each other during the course of treatment (e.g., adjusted up or down as necessary).

[0037] As used herein, the phrase "the immediately preceding dose" refers to a dose of a VEGF antagonist that is administered to a patient's eye in a sequential multiple administration prior to the administration of the immediately next sequential dose, without any intervening doses.

[0038] In one embodiment of the invention, the VEGF antagonist dosing regimen is carried out over the course of 24, 48, 52, 96 or 100 weeks (or more).

[0039] In one embodiment of the present invention, patients (e.g., suffering from NPDR) receiving such a dosing regimen show at least a two-step improvement in the DRSS (Diabetic Retinopathy Severity Scale) in the eye from baseline (before treatment begins) at 24, 48 or 52 weeks. In one embodiment of the present invention, a three-step improvement is experienced in the eye.

[0040] The method of the present invention can include administering any number of secondary and / or tertiary doses of VEGF antagonist to the patient's eye. For example, in certain embodiments, only a single secondary dose is administered to the patient's eye. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are administered to the patient's eye. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient's eye. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) tertiary doses are administered to the patient's eye.

[0041] In embodiments that include multiple secondary doses, each secondary dose is administered with the same frequency as other secondary doses. For example, each secondary dose is administered to the patient's eye 4 weeks after the previous dose. Similarly, in embodiments that include multiple tertiary doses, each tertiary dose is administered with the same frequency as other tertiary doses. For example, each tertiary dose is administered to the patient's eye 8 weeks after the previous dose. Alternatively, the frequency that secondary and / or tertiary doses are administered to the patient's eye may vary over the course of treatment regimen. For example, the invention includes a method comprising administering to a patient's eye a single initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by at least five tertiary doses of the VEGF antagonist, where the first four tertiary doses are administered 8 weeks after the immediately preceding dose, and each subsequent tertiary dose is administered 8 to 12 weeks (e.g., 8 weeks, 8 1 / 2 weeks, 9 weeks, 9 1 / 2 weeks, 10 weeks, 10 1 / 2 weeks, 11 weeks, 11 1 / 2 weeks, 12 weeks) after the immediately preceding dose. The frequency of administration may be adjusted by the physician according to the needs of the individual patient after consultation during the course of treatment.

[0042] In one embodiment of the present invention, the VEGF antagonist is administered to the subject in conjunction with an additional therapeutic agent (e.g., a vitamin or dietary supplement) or treatment procedure (e.g., laser therapy or surgery) according to the dosage regimen of the present invention. For example, in one embodiment of the present invention, the subject undergoes laser therapy, such as panretinal photocoagulation (laser) treatment, in conjunction with the VEGF antagonist. In one embodiment of the present invention, the subject has previously undergone laser therapy, for example to treat DR (e.g., PDR), but has switched to a VEGF antagonist dosage regimen according to the present invention.

[0043] The term "in association with" refers to an agent that is administered in conjunction with a component VEGF antagonist. It is indicated that the additional therapeutic agent is formulated in a single composition, for example for simultaneous delivery, or is formulated separately in two or more compositions (e.g., a kit). Each component can be administered to a subject at a different time than the other components are administered; for example, each administration is given at an interval over a given period of time, but not simultaneously (e.g., separately or sequentially). Furthermore, the separate components can be administered to a subject by the same route or by different routes.

[0044] VEGF antagonists The methods of the invention include administering to the patient's eye a VEGF antagonist according to the specific dosing regimens described herein. As used herein, the phrase "VEGF antagonist" refers to any molecule that blocks, reduces or interferes with the normal biological activity of VEGF.

[0045] A VEGF antagonist is a molecule that interferes with the interaction between VEGF and the natural VEGF receptor, e.g., a molecule that binds to VEGF or a VEGF receptor and inhibits the interaction between VEGF and the VEGF receptor. VEGF antagonists include molecules that prevent or otherwise interfere with the interaction between VEGF and VEGF receptor. Specific exemplary VEGF antagonists include anti-VEGF antibodies and antigen-binding fragments thereof (e.g., Fab or F(ab)2), anti-VEGF receptor antibodies and antigen-binding fragments thereof, anti-VEGF and anti-VEGF receptor single chain antibodies, anti-VEGF and anti-VEGF receptor bispecific antibodies and antigen-binding fragments thereof, anti-VEGF and anti-VEGF receptor DARPins (designed ankyrin repeat proteins), and VEGF receptor-based chimeric molecules (also referred to herein as "VEGF-Traps").

[0046] VEGF receptor-based chimeric molecules include chimeric polypeptides that contain two or more immunoglobulin (Ig)-like domains of a VEGF receptor, such as VEGFR1 (also referred to as Flt1) and / or VEGFR2 (also referred to as Flk1 or KDR), and may also contain a multimerization domain (e.g., an Fc domain that promotes multimerization [e.g., dimerization] of two or more chimeric polypeptides). An exemplary VEGF receptor-based chimeric molecule is a molecule designated VEGFR1R2-FcΔC1(a), which is encoded by the nucleic acid sequence of SEQ ID NO:1. VEGFR1R2-FcΔC1(a) comprises three components: (1) a VEGFR1 component comprising amino acids 27 through 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component ("FcΔC1(a)") comprising amino acids 232-457 of SEQ ID NO:2 (the C-terminal amino acid of SEQ ID NO:2 [i.e., K458] may or may not be included in the VEGF antagonists used in the methods of the invention; see, e.g., U.S. Patent No. 7,396,664). Amino acids 1-26 of SEQ ID NO:2 are a signal sequence.

[0047] The VEGF antagonist used in the examples described herein below is a molecule comprising a VEGFR1R2-FcΔC1(a) molecule (e.g., a homodimer thereof), and is referred to herein as "VEGFT". Additional VEGF receptor-based chimeric molecules that can be used in the context of the present invention are disclosed in U.S. Patent Nos. 7,396,664, 7,303,746 and WO 00 / 75319.

[0048] In one embodiment of the invention, the VEGF antagonist is: (1) immunoglobulin-like (Ig) domain 2 of the first VEGF receptor (e.g., VEGFR1); (2) Ig domain 3 of a second VEGF receptor (e.g., VEGFR2); and (3) a multimerization component (e.g., Fc or a variant thereof) and a VEGF receptor-based chimeric molecule which is a polypeptide (or homodimer thereof) comprising:

[0049] In one embodiment of the invention, the VEGF antagonist is: (1) immunoglobulin-like (Ig) domain 2 of the first VEGF receptor (e.g., VEGFR1); (2) Ig domain 3 of the second VEGF receptor (e.g., VEGFR2); (3) immunoglobulin-like (Ig) domain 4 of a second VEGF receptor (e.g., VEGFR2); and (4) a multimerization component (e.g., Fc or a variant thereof); and a VEGF receptor-based chimeric molecule which is a polypeptide (or homodimer thereof) comprising:

[0050] Exemplary VEGF antagonists for use in the context of the present invention include, for example, VEGF mini-Traps (see, e.g., U.S. Pat. No. 7,087,411), anti-VEGF DARPins such as aflibercept, Abicipar Pegol DARPin, single chain (e.g., VL-VH) anti-VEGF antibodies such as brolucizumab (RTH258), , monospecific, polyspecific or bispecific anti-VEGF antibodies or antigen-binding fragments thereof that also bind to ANG2, such as RG7716, ranibizumab (LUCENTIS) or bevacizumab (AVASTIN), and conbercept.

[0051] Angiogenic eye disorders The method of the present invention can be used to treat or prevent any angiogenic eye disorder by administering to the eye of the subject a therapeutically effective amount of VEGF antagonist (e.g., 2mg aflibercept) according to the dosing regimen described herein.As used herein, the phrase "angiogenic eye disorder" refers to any disease of the eye that is caused by or associated with the growth or proliferation of blood vessels or by vascular leakage. Non-limiting examples of angiogenic eye disorders that can be treated using the methods of the present invention include age-related macular degeneration (e.g., wet AMD, exudative AMD, etc.), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO; e.g., macular edema secondary to CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV; e.g., myopic CNV), iris neovascularization, neovascular glaucoma, post-operative fibrosis in glaucoma, proliferative vitreous retinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathies, and diabetic retinopathy, such as non-proliferative and proliferative diabetic retinopathy.

[0052] Diabetic retinopathy is a progressive condition that can occur in people with diabetes. Typically, it causes progressive damage to the retina, the light-sensitive lining at the back of the eye. Diabetic retinopathy is a serious, vision-threatening complication of diabetes. Over time, diabetes damages blood vessels in the retina, and diabetic retinopathy occurs when these tiny blood vessels leak blood and other fluids. The condition typically affects both eyes. The longer a person has diabetes, the more susceptible they are to developing diabetic retinopathy. If left untreated, diabetic retinopathy can result in blindness. Symptoms of diabetic retinopathy include: Visible spots or floating objects Blurred vision A dark or empty spot in the center of the field of vision Difficulty seeing at night Examples include:

[0053] Therefore, in order to preserve vision, it is important to halt or prevent the progression of diabetic retinopathy to its more vision-threatening later stages, such as proliferative diabetic retinopathy, diabetic macular edema, and / or anterior segment neovascularization (ASNV). Klein et al., Changes in Retinal Vessel Diameter and Incidence and Progression of Diabetic Retinopathy,Arch.Opthamol.130(6):749~755(2012)

[0054] Anterior segment neovascularization is defined as neovascularization of the iris and / or distinct neovascularization of the iridocorneal angle.

[0055] As diabetic retinopathy progresses, it can reach more advanced stages, including: 1. Mild nonproliferative retinopathy. This stage is characterized by small areas of ballooning in the tiny blood vessels of the retina, called microaneurysms. These microaneurysms may leak fluid into the retina; then 2. Moderate nonproliferative retinopathy. As the disease progresses, the blood vessels that nourish the retina swell and become distorted. They may also lose their ability to transport blood. Both conditions produce characteristic changes in the appearance of the retina and may contribute to diabetic macular edema; 3. Severe nonproliferative retinopathy. In this stage, more blood vessels are blocked, starving areas of the retina of blood supply. These areas secrete growth factors that signal the retina to grow new blood vessels; then 4. Proliferative diabetic retinopathy (PDR). Please see below.

[0056] Nonproliferative diabetic retinopathy (NPDR) is an early stage retinopathy in diabetic patients that is not characterized by neovascularization and whose stages are also graded according to the Diabetic Retinopathy Severity Scale (DRSS). Grades of NPDR include, for example, early, moderate, moderate and severe. In one embodiment of the present invention, moderate to severe NPDR corresponds to a severity level of 47 to 53 (e.g., 47 or 53). In one embodiment of the present invention, a patient (e.g., a human, e.g., aged 18 years or older, having type 1 or 2 diabetes) with moderate to severe NPDR is characterized using one or more of the following: · Not having macular edema (e.g., threatening the center of the macula); · Panretinal photocoagulation can be safely postponed for at least 6 months; · Have a baseline best-corrected visual acuity (BCVA) ETDRS letter score of 69 or greater (e.g., Snellen acuity of 20 / 40 or better); · No retinal neovascularization; · No anterior segment neovascularization (ASNV); No vitreous hemorrhage; and / or No tractional retinal detachment.

[0057] Proliferative diabetic retinopathy (PDR) is a more advanced form of diabetic retinopathy. At this stage, new fragile blood vessels may begin to grow in the retina and into the vitreous, a gel-like fluid that fills the back of the eye. The new blood vessels may leak blood into the vitreous, causing vision to become clouded.

[0058] Thus, the present invention includes a method for treating or preventing diabetic retinopathy in a subject's eye by administering a VEGF antagonist (e.g., aflibercept 2 mg) under the dosage regimen described herein to the eye of the subject, regardless of whether the eye of the subject has moderate NPDR (non-proliferative diabetic retinopathy) or severe NPDR (e.g., moderate to severe NPDR) or PDR (proliferative diabetic retinopathy), for example, the DRSS for diabetic retinopathy of the subject is 47 or 53. In one embodiment of the present invention, the subject does not suffer from diabetic macular edema (DME) and / or central-comprising diabetic macular edema (CI-DME). In patients with non-proliferative diabetic retinopathy, the dosage regimen described herein is used to prevent the progression of the patient to more severe forms of NPDR or to proliferative diabetic retinopathy, ASNV, DME and / or CI-DME. Indeed, the dosing regimen of the present invention is used to reverse (or prevent) an increase in DRSS, e.g., by 2 or more levels, e.g., by as much as 3 levels, in patients suffering from NPDR (e.g., not suffering from DME and / or CI-DME).

[0059] The International Clinical Diabetic Retinopathy Disease Severity Scale (DRSS), including its levels, is detailed in the table set forth in FIG.

[0060] Subjects with NPDR are at risk for a variety of sight-threatening complications or events (VTCs) and blindness (e.g., blindness secondary to such VTCs). Sight-threatening complications are defined as the composite outcome of PDR (including patients with vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and ASNV. ASNV is defined as neovascularization of the iris (at least 2 cumulative clock hours) and / or distinct neovascularization of the iridocorneal angle. Dosing regimens are used to assess the efficacy and safety of NPDR in subjects with NPDR. The present invention thus provides a method for preventing the onset or recurrence of VTC (following one or more initial episodes) and / or blindness in a subject suffering from, for example, NPDR or PDR, by administering a VEGF antagonist (aflibercept, for example, 2.0 mg) to the eye of the subject under the dosing regimen described herein. Such a method includes not only treating one eye suffering from VTC, but also treating the other eye to prevent VTC and / or blindness, even if the other eye does not suffer from VTC and / or blindness.

[0061] Pharmaceutical preparations The present invention includes a method in which the VEGF antagonist administered to the eye of a patient is contained in a pharmaceutical formulation. The pharmaceutical formulation may include the VEGF antagonist together with at least one inactive ingredient, such as, for example, a pharma- ceutically acceptable carrier. Other agents are incorporated into the pharmaceutical composition to provide improved transfer, delivery, tolerability, and the like. The term "pharmaceutical acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more specifically in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody is administered. Many suitable formulations can be found in formularies well known to compounding pharmacists: Remington's Pharmaceutical Sciences (15th Edition), ed., 1999; 1999; 1999; 1999; 2000; 2001; 2002; 2003; 2004; 2005; 2006; 2007; 2008; 2009; 2010; 2010; 2011; th ed., Mack Publishing Company, Easton, Pa., 1975), particularly Chapter 87 therein by Blaug and Seymour. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vehicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, and the like. pastes), oil-in-water and water-in-oil emulsions, emulsion carbowaxes (various Examples of suitable excipients and carriers include semi-solid mixtures containing polyethylene glycol of molecular weight 0.1 to 100 g, semi-solid gels and carbowax. Any of the aforementioned mixtures may be suitable in the context of the methods of the present invention, so long as the VEGF antagonist is not inactivated by the formulation and the formulation is physiologically compatible with the route of administration and tolerated. See also Powell et al. PDA (1998) J Pharm Sci Technol. 52:238-311 and citations therein for additional information regarding excipients and carriers well known to compounding pharmacists.

[0062] Pharmaceutical preparations useful for administration by injection in the context of the present invention can be prepared by dissolving, suspending or emulsifying VEGF antagonist in sterile aqueous or oily medium conventionally used for injection.Aqueous medium for injection includes, for example, physiological saline, isotonic solution containing glucose, and other auxiliary agents that can be used together with suitable solubilizing agents such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)].Oil medium can include, for example, sesame oil, soybean oil, etc., that can be used together with solubilizing agents such as benzyl benzoate, benzyl alcohol, etc.The injection thus prepared can be filled into suitable ampoules as required.

[0063] In one embodiment of the invention, the pharmaceutical formulation administered to the subject comprises aflibercept, for example about 40 mg / mL aflibercept in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20 and 5% sucrose, pH 6.2.

[0064] In one embodiment of the invention, the pharmaceutical formulation administered to the subject comprises a VEGF antagonist (e.g., aflibercept or conbercept, e.g., 40 mg / ml thereof) and: (a) pyrophosphate (e.g., 5 mM to 250 mM). In one embodiment of the invention, the formulation comprises: Further containing NaCl, sodium citrate, citric acid, mannitol and polysorbate 80, e.g., pH 5.2; (b) buffers, such as histidine salts, such as histidine-HCl or histidine-acetate (e.g., 10 mM to 50 mM), e.g., pH 5.7 to 6.2; sugars, such as sucrose, trehalose, mannitol or glucose (e.g., greater than 6% but less than or equal to 10%, e.g., 2.5% to 10%); and detergents, such as polysorbate 20 and polysorbate 80 (e.g., 0% or 0.01% to 0.03%); (c) histidine-containing buffers such as L-histidine / histidine hydrochloride; non-ionic surfactants such as polysorbate 20 (e.g., 0.03%), inorganic salts such as NaCl (e.g., 40 mM) and carbohydrates such as sucrose (e.g., 5%), for example, pH 6.0-6.5 (e.g., 6.2 or 6.5); (d) a buffer consisting of a histidine salt (e.g., the histidine salt is histidine-HCl or histidine-acetate, e.g., 10 mM to 50 mM) and having a pH range of 5.7 to 6.2; a sugar selected from the group consisting of sucrose, trehalose, mannitol and glucose (e.g., greater than 6% but not greater than 10%); a surfactant selected from the group consisting of polysorbate 20 and polysorbate 80 (e.g., 0% to 0.1%); (e) citric acid (e.g., 5 mM, 10 mM, 15 mM, 20 mM, 25 mM or 30 mM), sucrose (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%), arginine (e.g., 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM or 50 mM or 100 mM) and polysorbate 20 (e.g., 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09% or 0.10%); (f) phosphate, histidine, acetate, succinate, citric acid, buffers such as glutamic acid and / or lactic acid (e.g., 5-20 or 5-50 mM); non-ionic surfactants such as polysorbates (e.g., PS20 or PS80), polyethylene glycol dodecyl ether, poloxamers, 4-(l,l,3,3-tetramethylbutyl)phenyl-polyethylene glycol, alkyl saccharides or alkyl glycosides, tonicifying agents such as polyols or amino acids, e.g., sucrose, trehalose, sorbitol, mannitol, glycerin, proline, arginine, methionine, glycine or lysine, the formulation having a final osmolality of about 300 mOsm / kg, chloride The concentration of the product anion is less than about 10 mM; pH 5.0-6.5; (g) sodium acetate (e.g., 10-15 mM); sucrose (e.g., 7%) or trehalose (e.g., 8%); and polysorbate 20 (e.g., 0.03%), pH 5.5; or (h) 10 mM sodium phosphate, 40 mM sodium chloride, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, pH 6.2; 10 mM sodium phosphate, 9% (w / v) sucrose, 0.03% (w / v) polysorbate 20, pH 6.2; 10 mM sodium phosphate, 40 mM sodium chloride, 2% (w / v) proline, 0.03% (w / v) polysorbate 20, pH 6.2; 10 mM sodium phosphate, 3% (w / v) proline, 0.03% (w / v) polysorbate 20, pH 6.2 sorbate 20, pH 6.2; 10 mM sodium phosphate, 9% (w / v) trehalose, 0.03% (w / v) polysorbate 20, pH 6.2; 10 mM histidine, 3% (w / v) proline, 0.03% (w / v) polysorbate 20, pH 6.2; 10 mM histidine, 9% (w / v) sucrose, 0.03% (w / v) polysorbate 20, pH 6.2; or 10 mM acetic acid, 9% (w / v) sucrose, 0.03% (w / v) polysorbate 20, pH 5.2. Includes.

[0065] Mode of administration The VEGF antagonist (or a pharmaceutical formulation containing the VEGF antagonist) can be administered to a patient by any known delivery system and / or administration method. In certain embodiments, the VEGF antagonist is administered to the patient by ocular, intraocular, intravitreal or subconjunctival injection. In other embodiments, the VEGF antagonist can be administered to the patient by topical administration, for example, via eye drops or other liquids, gels, ointments or fluids containing the VEGF antagonist, and can be applied directly to the eye. Administration to the patient's or subject's eye refers to any acceptable method (e.g., intravitreal injection) for delivering a VEGF antagonist (e.g., aflibercept) to the ocular tissue of the patient or subject. In one embodiment of the present invention, administration to the patient's or subject's eye refers to delivering a VEGF antagonist to the eye that is suffering from an angiogenic eye disorder such as NPDR (e.g., as discussed herein), and optionally to the other eye, even if it is not suffering from the condition. In one embodiment of the present invention, administration is intravitreal injection using a syringe with a 30 gauge, 0.5 inch needle. For example, in one embodiment of the present invention, about 50 μl is injected intravitreally to deliver about 2 mg of VEGF antagonist (e.g., aflibercept; e.g., about 40 mg / mL aflibercept in a pharmaceutical formulation containing aflibercept, e.g., in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20 and 5% sucrose pH 6.2). In one embodiment of the present invention, 0.5 or 2.0 mg of conbercept in a pharmaceutical formulation containing conbercept, citric acid, sucrose, arginine and polysorbate 20 is injected into the eye.

[0066] Other possible routes of administration include, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral. When such routes of administration are used, delivery is not to the eye but to another tissue, such as the skin, muscle tissue, peritoneum, vein, subcutaneous tissue, nasal cavity, dura or oral cavity.

[0067] Amount of VEGF antagonist administered Each dose of VEGF antagonist (e.g., aflibercept, e.g., 0.5 mg or 2 mg) administered to the patient's eye over the course of a treatment regimen can contain the same or substantially the same amount of VEGF antagonist. Alternatively, the amount of VEGF antagonist contained in each dose can vary over the course of a treatment regimen. For example, in certain embodiments, a first amount of VEGF antagonist is administered in a first dose, a second amount of VEGF antagonist is administered in a second dose, and a third amount of VEGF antagonist is administered in a third dose. The present invention contemplates a dosing scheme in which the amount of VEGF antagonist contained in each dose increases over time (e.g., each subsequent dose contains more VEGF antagonist than the last one), decreases over time (e.g., each subsequent dose contains less VEGF antagonist than the last one), increases first and then decreases, decreases first and then increases, or remains the same throughout the course of a dosing regimen.

[0068] The amount of VEGF antagonist administered to the patient's eye in each dose (e.g., 0.5 mg or 2 mg of aflibercept or conbercept) is in most cases a therapeutically effective amount.As used herein, the phrase "therapeutically effective amount" refers to the dose of VEGF antagonist that causes detectable improvement in one or more symptoms or signs of angiogenic eye disorder, or the dose of VEGF antagonist that inhibits, prevents, slows down or retards the progression of angiogenic eye disorder. In the case of an anti-VEGF antibody or a VEGF receptor-based chimeric molecule, such as VEGFR1R2-FcΔC1(a), a therapeutically effective amount is about 0.05 mg to about 5 mg of the antibody or receptor-based chimeric molecule, e.g., about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg. g, about 1.5 mg, about 1.55 mg, about 1.6 mg, about 1.65 mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 1.85 mg, about 1.9 mg, about 2.0 mg, about 2.05 mg, about 2.1 mg, about 2.15 mg, about 2.2 mg, about 2.25 mg, about 2.3 mg, about 2.35 mg, about 2.4 mg, about 2.45 mg, about 2.5 mg, about 2.55 mg, about 2.6 mg, about 2.65 mg, about 2.7 mg, about 2.75 mg, about 2.8 mg, about 2.85 mg, about 2.9 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg or about 5.0 mg.

[0069] The amount of VEGF antagonist contained in each dose is expressed in milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the VEGF antagonist is administered to a patient at a dose of about 0.0001 to about 10 mg / kg of the patient's body weight.

[0070] Treatment Population and Indication The methods of the present invention are useful for treating angiogenic eye disorders in patients diagnosed with or at risk of suffering from angiogenic eye disorders. In general, the methods of the present invention demonstrate efficacy within 104 weeks of initiating a treatment regimen (from the first dose administered at "week 0"), for example, by the end of week 16, by the end of week 24, by the end of week 32, by the end of week 40, by the end of week 48, by the end of week 52, by the end of week 56, etc.

[0071] In one embodiment of the present invention, in the context of a method for treating angiogenic eye disorders such as DR, PDR, NPDR, AMD, CRVO and DME, "efficacy" refers to the degree to which a patient achieves, from the start of treatment: Loss of 15 or fewer letters (e.g., 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1) on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart; Gain of one or more letters (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more) on the ETDRS chart; Maintenance or improvement in DRSS score, e.g., reduction of 2 or 3 steps on the DRSS; Reducing or preventing the development of vision-threatening complications (VTCs) and / or blindness and / or central diabetic macular edema; and / or · Reduction or maintenance of central retinal thickness; indicates, For example, one or more of such goals may be achieved within about 24 or 52 weeks of initiating treatment. This means that...

[0072] package One aspect of the present invention is: Drug containers; and In the patient's eyes, Approximately 2 mg of VEGF antagonist, a VEGF receptor-based chimeric molecule (i) 3 monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 5 monthly doses followed by one or more secondary doses every 8 weeks; instructions for using the drug to treat or prevent diabetic retinopathy in a patient in need of treatment, showing use of the drug by administering the drug of This is a package that includes:

[0073] Another aspect of the present invention is a method for producing a VEGF antagonists are (i) comprises: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232 to 457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) conbercept, It is a package.

[0074] Another aspect of the invention is a package where the instructions indicate that the drug is administered by intravitreal injection.

[0075] In another embodiment of the invention, the instructions indicate that the drug is to be administered in 3 or 5 monthly doses, followed by one or more doses every 8 weeks.

[0076] In another embodiment of the invention, the instructions indicate that the drug is to be administered in three monthly doses, followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks after the third monthly dose (at week 16).

[0077] Another embodiment of the invention is a package where the instructions indicate that the drug is to be administered in one dose every eight weeks.

[0078] Aspects of the present invention include: Drug containers; and In the patient's eyes, Approximately 2 mg of VEGF antagonist, a VEGF receptor-based chimeric molecule (i) 3 monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 5 monthly doses followed by one or more secondary doses every 8 weeks; instructions for using the drug to treat or prevent proliferative diabetic retinopathy in a patient in need of treatment, showing use of the drug by administering the drug of This is a package that includes:

[0079] In another aspect of the invention, the VEGF antagonist is (i) comprises: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232 to 457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) conbercept, It is a package.

[0080] Working Example The examples which follow are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy, but some experimental error and deviation should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0081] The exemplary VEGF antagonist used in all examples described below (unless otherwise indicated) is a dimeric molecule with two functional VEGF binding units. Each functional binding unit is composed of Ig domain 2 from VEGFR1 fused to Ig domain 3 from VEGFR2, which is then fused to the hinge region of a human IgG1 Fc domain (VEGFR1R2-FcΔC1(a); encoded by SEQ ID NO:1). This VEGF antagonist is referred to as "VEGFT" in the following examples. For the purposes of the following examples, "monthly" dosing is equivalent to dosing once every four weeks. EXAMPLES

[0082] Phase I clinical trial of intravitreally administered VEGF receptor-based chimeric molecule (VEGFT) in subjects with neovascular AMD In this Phase I study, 21 subjects with neovascular AMD received a single intravitreal (IVT) dose of VEGFT. Five groups of three subjects received either 0.05, 0.15, 0.5, 2, or 4 mg of VEGFT each, and a sixth group of six subjects received 1 mg. There were no serious adverse events with study drug, and no identifiable endophthalmitis was reported. Preliminary results showed sustained reductions in foveal thickness through six weeks following injection of VEGFT. At day 43 across all treatment groups, mean excess retinal thickness on optical coherence tomography (OCT) [excess retinal thickness = (retinal thickness - 179μ)] was significantly greater than mean excess retinal thickness on fast macular scan (FMS). The evaluation by single posterior pole scan showed a change from 119μ to 27μ. The best corrected visual acuity (BCVA) was reduced from 194μ to 60μ using the CT scan. The mean gain was 4.75 letters, and BCVA remained stable or improved in 95% of subjects. In the two higher dose groups (2 and 4 mg), 3 of 6 subjects demonstrated an improvement of >= 3 lines, for a mean gain in BCVA of 13.5 letters. EXAMPLES

[0083] A Phase II Clinical Trial of Multiple Doses of Intravitreally Administered VEGF Receptor-Based Chimeric Molecule (VEGFT) in Subjects with Neovascular AMD The study was a double-blind randomized study of three doses of VEGFT (0.5, 2, and 4 mg) examined at 4-week and / or 12-week dosing intervals. The study had five treatment arms: 1) 0.5 mg every 4 weeks, 2) 0.5 mg every 12 weeks, 3) 2 mg every 4 weeks, 4) 2 mg every 12 weeks, and 5) 4 mg every 12 weeks. Subjects were dosed at fixed intervals for the first 12 weeks and then evaluated every 4 weeks for 9 months, during which additional doses were administered based on prespecified criteria. All subjects were then followed for one year after their last dose of VEGFT. Preliminary data from a preplanned interim analysis showed that VEGFT met the primary endpoint of a statistically significant reduction in retinal thickness after 12 weeks compared to baseline (a reduction of 135μ for all groups combined, p<0.0001). The mean change from baseline in visual acuity, the study's key secondary endpoint, also demonstrated a statistically significant improvement (5.9 letter increase for all groups combined, p<0.0001). Additionally, patients in the dose group that received only a single dose demonstrated a mean reduction in excess retinal thickness (p<0.0001) and increase in visual acuity (p=0.012) at 12 weeks. There were no drug-related serious adverse events, and treatment with the VEGF antagonist was generally well tolerated. The most frequent adverse events were those typically associated with intravitreal injections. EXAMPLES

[0084] Phase I clinical trial of a systemically administered VEGF receptor-based chimeric molecule (VEGFT) in subjects with neovascular AMD This study was a placebo-controlled, sequential-group, dose-escalation safety, tolerability, and bioefficacy study of VEGFT by IV infusion in subjects with neovascular AMD. Groups of eight subjects who met eligibility criteria for AMD-associated subfoveal choroidal neovascularization (CNV) were assigned to receive four IV infusions of VEGFT or placebo at dose levels of 0.3, 1, or 3 mg / kg over an 8-week period.

[0085] Most adverse events attributable to VEGFT were mild to moderate in severity, but two of five subjects treated with 3 mg / kg experienced dose-limiting toxicities (DLTs) (one with grade 4 hypertension and one with grade 2 proteinuria); therefore, all subjects in the 3 mg / kg dose group were removed from the study. The mean percent changes in excess retinal thickness were: -12%, -10%, -66%, and -60% (ANOVA p<0.02) for placebo, 0.3, 1, and 3 mg / kg dose groups at day 15, and -5.6%, +47.1%, and -63.3% (ANOVA p<0.02) for placebo, 0.3, and 1 mg / kg dose groups at day 71. There was a numerical improvement in BCVA in subjects treated with VEGFT. As expected in such a small study, the results were not statistically significant. EXAMPLES

[0086] A Phase III Clinical Trial of the Efficacy, Safety, and Tolerability of Repeat Doses of Intravitreal VEGFT in Subjects with Neovascular Age-Related Macular Degeneration A. Objectives, Hypotheses and Endpoints Two parallel Phase III clinical trials were conducted to investigate the use of VEGFT to treat patients with neovascular forms of age-related macular degeneration (Study 1 and Study 2). The primary objective of these studies was to evaluate the efficacy of IVT-administered VEGFT compared to ranibizumab (Lucentis®, Genentech, Inc.) in preventing moderate vision loss in subjects with all subtypes of neovascular AMD in a non-inferiority paradigm.

[0087] The secondary objectives were (a) to evaluate the safety and tolerability of repeat IVT administration of VEGFT for periods up to 2 years in subjects with all subtypes of neovascular AMD; and (b) to evaluate the effect of repeat IVT administration of VEGFT on vision-related quality of life (QOL) in subjects with all subtypes of neovascular AMD.

[0088] The primary hypothesis of these studies was that the proportion of subjects treated with VEGFT with stable or improved BCVA (<15 letter loss) would be similar to the proportion treated with ranibizumab with stable or improved BCVA, thereby demonstrating non-inferiority.

[0089] The primary endpoint of these studies was to prevent a loss of 15 or more letters of vision on the ETDRS chart at week 52 compared to baseline. Secondary endpoints were: (a) change from baseline to week 52 in ETDRS letter score; (b) gain of 15 or more letters on the ETDRS chart from baseline to week 52; (c) change in total NEI VFQ-25 score from baseline to week 52; and (d) change in CNV area from baseline to week 52.

[0090] B. Study Design For each study, subjects were assigned to one of four dosing regimens: (1) VEGFT 2 mg every 4 weeks; (2) VEGFT 0.5 mg every 4 weeks (0.5Q4); (3) VEGFT 2 mg every 4 weeks until week 8 then every 8 weeks, including a sham injection at the intervening 4-week visit where no study drug was administered (2Q8); and (4) ranibizumab 0.5 mg every 4 weeks (RQ4). Subjects assigned to (2Q8) received 2 mg injections every 4 weeks until week 8, then a sham injection at the intervening 4-week visit (where no study drug was administered) during the first 52 weeks of the study (sham injections were not given at week 52).

[0091] Study duration for each subject was planned to be 96 weeks plus the recruitment period. For the first 52 weeks (1 year), subjects received IVT or sham injections in the study eye every 4 weeks (sham injections were not given at week 52). During the second year of the study, subjects were evaluated every 4 weeks and received IVT injections of study medication at intervals determined by specific dosing criteria but at least every 12 weeks (sham injections were not given during the second year of the study). During this period, injections are given no more than every 4 weeks, but no less frequently than every 12 weeks, according to the following criteria: (i) an increase in central retinal thickness of ≥ 100 μm compared to the previous lowest value as measured by optical coherence tomography (OCT); or (ii) a loss of at least 5 ETDRS letters from the previous best letter score with recurrence of fluid as shown by OCT; or (iii) new or persistent fluid as shown by OCT; or (iv) new onset of typical neovascularization or new or persistent leakage on fluorescein angiography (FA); or (v) new macular hemorrhage; or (vi) 12 weeks have passed since the previous injection. According to this protocol, subjects must receive an injection at least every 12 weeks.

[0092] Subjects were evaluated at 4-week intervals for safety and best corrected visual acuity (BCVA) using the 4-meter ETDRS protocol. Quality of life (QOL) was assessed using the NEI VFQ-25 questionnaire. OCT and FA studies were performed periodically.

[0093] Approximately 1200 subjects were enrolled, with a target enrollment of 300 subjects per treatment arm.

[0094] To be eligible for the study, subjects had to have subfoveal choroidal neovascularization (CNV) secondary to AMD. "Subfoveal" CNV is defined as the presence of subfoveal neovascularization documented by FA or the presence of lesions that are angiographically juxtafoveal in location but affect the fovea. Subject eligibility was confirmed based on angiographic criteria prior to randomization.

[0095] Only one eye was designated as the study eye. For subjects who met the eligibility criteria in both eyes, the eye with the worse VA was selected as the study eye. If both eyes had equal VA, the eye with the clearer lens and ocular media and the lesser amount of subfoveal scarring or geographic atrophy was selected. In the absence of objective basis for selecting the study eye, factors such as ocular dominance, other ocular pathology, and study priority were considered in making the selection.

[0096] Inclusion criteria for both studies were: (i) signed informed consent; (ii) age at least 50 years; (iii) active primary subfoveal CNV lesions secondary to AMD, including juxtafoveal lesions affecting the fovea, as evidenced by FA in the study eye; (iv) CNV of at least 50% of the total lesion size; (v) Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity in the study eye: 20 / 40 to 20 / 320 (letter score of 73 to 25); (vi) willing, engaged, and able to return to all visits and complete all study-related procedures; and (vii) read, understand, and willingly sign the informed consent form (or, if unable to read due to vision impairment, have it read verbatim by the person administering the informed consent or a family member). You can receive it.

[0097] Exclusion criteria for both studies were: 1. Previous ocular (in the study eye) or systemic treatment or surgery for neovascular AMD, excluding dietary supplements or vitamins. 2. Previous or concurrent treatment with another investigational agent to treat neovascular AMD in the study eye, excluding dietary supplements or vitamins. 3. Previous treatment with the following anti-VEGF agents: (a) Previous treatment with an anti-VEGF treatment in the study eye was not allowed; (b) Previous treatment with an anti-VEGF treatment in the fellow eye with an investigational agent (not FDA approved, e.g., bevacizumab) was allowed up to 3 months prior to the first dose in the study, and such treatment was not allowed during the study. Previous treatment with an approved anti-VEGF treatment in the fellow eye was allowed; (c) Previous systemic anti-VEGF treatment, in a clinical trial or FDA / Health Canada approved, was only allowed up to 3 months prior to the first dose, and was not allowed during the study. 4. Total lesion size >12 disc areas (30.5 mm2, including blood, scar and neovascularization) assessed by FA in the study eye. 5. Subretinal hemorrhage in the study eye that is either 50% or more of the total lesion area or 1x the disc area in size if blood is subfoveal (if blood is subfoveal, the fovea must be surrounded 270 degrees by visible CNV). 6. Scar or fibrosis constituting >50% of the total lesion in the study eye. 7. Scar, fibrosis or atrophy involving the center of the fovea. 8. Presence of a tear or break in the retinal pigment epithelium involving the macula in the study eye. 9. History of vitreous hemorrhage within 4 weeks prior to Visit 1 in the study eye. 10. Presence of other causes of CNV in the study eye including pathologic myopia (-8 diopters or more negative spherical equivalent or axial length ≥ 25 mm), ocular histoplasmosis syndrome, pigmented streaks, choroidal rupture or multifocal choroiditis. 11. History or clinical evidence of diabetic retinopathy, diabetic macular edema or other vascular disease affecting the retina other than AMD in either eye. 12. Previous vitrectomy in the study eye. 13. History of retinal detachment or procedure or surgery for retinal detachment in the study eye. 14. History of macular hole stage 2 or greater in the study eye.15. Intraocular or periocular surgery in the study eye within 3 months prior to Day 1, excluding eyelid surgery not performed within 1 month prior to Day 1, as long as it is unlikely to interfere with the injection. 16. Previous trabeculectomy or other filtration surgery in the study eye. 17. Uncontrolled glaucoma (defined as intraocular pressure ≥ 25 mmHg despite treatment with anti-glaucoma medications) in the study eye. 18. Active endophthalmitis in either eye. 19. Active bulbar or periocular infection in either eye. 20. Bulbous or periocular infection within 2 weeks prior to screening in either eye. 21. History of uveitis in either eye. 22. Active scleritis or episcleritis in either eye. 23. Presence or history of scleromalacia in either eye. 24. Aphakia or pseudophakia with no posterior capsule (other than as a result of yttrium-aluminum-garnet [YAG] posterior capsulotomy) in the study eye. 25. Previous radiation therapy in the area of ​​the study eye. 26. History of corneal transplant or corneal dystrophy in the study eye. 27. Significant opacification of the media, including cataract, in the study eye that may interfere with visual acuity, safety assessments or fundus photography. 28. Any medication, in the investigator's opinion, during the 96-week study period. or surgical intervention (e.g., cataract). 29. Concurrent ocular conditions in the target eye that, in the investigator's opinion, may increase risk to the subject beyond that expected from standard procedures for intraocular injections or that may otherwise interfere with the injection procedure or the evaluation of efficacy or safety. 30. History of other diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings that give reasonable suspicion of a disease or condition that contraindicates use of the investigational product or that may affect interpretation of the results of the study or place the subject at high risk of treatment complications. 31. Participation as a subject in any clinical trial within 12 weeks prior to Day 1. 32. Systemic or ocular treatment with an investigational product within the past 3 months prior to Day 1. 33. Use of long-acting steroids, either systemic or intraocular, within the past 6 months prior to Day 1. 34. Povidone History of allergy to iodine. 35. Known severe allergy to sodium fluorescein for angiographic injection. 36. Presence of any contraindication listed in the FDA-approved label for ranibizumab (Lucentis®). 37. Pregnant, breastfeeding, or females of childbearing potential who are not willing to practice adequate contraception throughout the study period. Appropriate contraceptive methods include oral contraceptives (stable use for at least two menstrual cycles prior to screening); IUD; Depo-Provera®; Norplant® System implant; bilateral tubal ligation; vasectomy; condoms or diaphragms plus either contraceptive sponges, foams, or gels.

[0098] Subjects were not permitted to receive any standard or investigational agents other than the protocol-specified assigned study treatment with VEGFT or ranibizumab for the treatment of their AMD in the study eye until they completed the Completion / Early Discontinuation Visit evaluation, including medications administered locally (e.g., IVT, topical, juxtascleral, or periorbital routes) and those administered systemically with the intent of treating the study and / or fellow eye.

[0099] The study procedures are summarized below:

[0100] Best corrected visual acuity: Visual function of the study eye and fellow eye was assessed using the ETDRS protocol (Early Treatment Diabetic Retinopathy Study Group) at 4 meters. Visual acuity examiners were certified to ensure consistent measurements of BCVA. VA examiners were asked to remain masked to treatment allocation.

[0101] Optical coherence tomography: Retinal and lesion characteristics were assessed using OCT in the study eye. Images were recorded and transmitted for both eyes at the screening visit (Visit 1). All OCT images were recorded using a Zeiss Stratus OCT™ with software version 3 or later. OCT images were sent to an independent reading center where images were read by masked readers at visits where OCT was required. All OCTs were electronically archived at the facility as part of the source documentation. A subset of OCT images were read. OCT technicians were required to be certified by the reading center to ensure consistency and quality in image collection. Substantial efforts were made to ensure that the facility's OCT technicians remained masked to treatment allocation.

[0102] Fundus Photography and Fluorescein Angiography (FA): The anatomical status of the retinal vasculature of the study eyes was assessed by fundus examination, fundus photography, and FA. Fundus examination, fundus photography, and FA were recorded and sent for both eyes at the screening visit (Visit 1). Fundus and angiographic images were sent to an independent reading center where the images were read by masked readers. The reading center confirmed subject eligibility based on angiographic criteria before randomization. All FA and fundus photographs were archived at the institution as part of the source documentation. Photographers were required to be authenticated by the reading center to ensure consistency and quality in image collection. Substantial efforts were made to ensure that all photographers at the institution remained masked to treatment allocation.

[0103] Vision-Related Quality of Life: Vision-related quality of life was assessed using the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) in an interviewer-administered format. The NEI VFQ-25 was administered by certified personnel at a contracted call center. At the screening visit, the site assisted subjects and initiated the initial call to the call center, collected contact information for all subjects, and completed the initial NEI VFQ-25 over the phone prior to randomization and IVT injection. All subsequent visits For each study, a call center called subjects and had them complete a questionnaire before the IVT injection.

[0104] Intraocular Pressure: Intraocular pressure (IOP) in the subject eyes was measured using applanation tonometry or Tonopen. The same IOP measurement method was used in each subject throughout the study.

[0105] C. Summary of Results (52-week data) The primary endpoint (prevention of moderate or severe vision loss as defined above) was met for all three VEGFT arms (2Q4, 0.5Q4, and 2Q8) in this study. Results from both studies are summarized in Table 1.

[0106] [Table 1]

[0107] In Study 1, patients receiving VEGFT 2 mg monthly (2Q4) achieved a statistically significantly greater mean improvement in visual acuity versus baseline at week 52 compared with ranibizumab 0.5 mg monthly (RQ4) (secondary endpoint); patients receiving VEGFT 2 mg monthly gained a mean of 10.9 letters compared with a mean gain of 8.1 letters with ranibizumab 0.5 mg dosed monthly (p<0.01). All other dose groups of VEGFT in Study 1 and all dose groups in Study 2 were not statistically different from ranibizumab in this secondary endpoint.

[0108] A generally favorable safety profile was observed for both VEGFT and ranibizumab. The incidence of ocular treatment-emergent adverse events was balanced across all four treatment arms in both studies with the most frequent events related to the injection procedure, underlying disease and / or aging. The most frequent ocular adverse events were conjunctival hemorrhage, macular degeneration, eye pain, retinal hemorrhage and vitreous floaters. The most frequent serious non-ocular adverse events were typical of those reported in elderly populations receiving intravitreal treatment for wet AMD; the most frequent events reported were falls, pneumonia, myocardial infarction, atrial fibrillation, breast cancer and acute coronary syndrome. There were no notable differences within the study arms. EXAMPLES

[0109] A Phase II Clinical Trial of VEGFT in Subjects with Diabetic Macular Edema (DME) In this study, patients with clinically significant DME including central macular involvement were 221 patients were randomized and 219 patients were treated with a balanced distribution across the five groups. The control group received macular laser therapy at baseline, and patients were eligible for repeat laser treatments but not more frequently than at 16-week intervals. The remaining four groups received VEGFT by intravitreal injection as follows: two groups received VEGFT 0.5 or 2 mg once every 4 weeks throughout the 12-month dosing period (0.5Q4 and 2Q4, respectively). Two groups received three initial doses of VEGFT 2 mg once every 4 weeks (i.e., baseline and weeks 4 and 8), followed by dosing once every 8 weeks (2Q8) through week 52 or as needed (PRN) with very strict repeat dosing criteria. The mean increase in visual acuity versus baseline is shown in Table 2:

[0110] [Table 2]

[0111] In this study, visual acuity gains achieved with VEGFT treatment at week 24 were maintained or numerically improved through study completion at week 52 in all VEGFT study arms, including the 2 mg every other month dose.

[0112] As demonstrated in the preceding examples, administration of VEGFT once every eight weeks to patients suffering from angiogenic eye disorders (e.g., AMD and DME), followed by a single initial dose and two secondary doses administered four weeks apart, resulted in significant prevention of moderate or severe vision loss or improvement in vision. EXAMPLES

[0113] A randomized, multicenter, double-blind clinical trial in treatment-naive patients with macular edema secondary to CRVO In this randomized, double-blind, phase 3 study, patients received six monthly injections of either intravitreal VEGFT 2 mg (114 patients) or sham injections (73 patients). From weeks 24 to 52, all patients received VEGFT as needed (PRN) according to retreatment criteria. 2 mg. Thus, "sham-treated patients" refer to patients who received one sham injection every 4 weeks from week 0 to week 20, followed by intravitreal VEGFT as needed from week 24 to week 52. Mean patients received one intravitreal VEGFT injection every 4 weeks through week 24, followed by intravitreal VEGFT as needed from week 24 through week 52. The primary endpoint was the proportion of patients with a ≥ 15 ETDRS letter increase from baseline to week 24. Secondary visual, anatomical and quality of life NEI VFQ-25 outcomes at weeks 24 and 52 were also assessed.

[0114] At week 24, 56.1% of VEGFT-treated patients versus 12.3% of sham-treated patients gained ≥15 ETDRS letters from baseline (P<0.0001). Similarly, at week 52, 55.3% of VEGFT-treated patients versus 30.1% of sham-treated patients gained ≥15 letters (P<0.01). At week 52, VEGFT-treated patients gained a mean of 16.2 letters versus 3.8 letters for sham-treated patients (P<0.001). The mean number of injections was 2.7 for VEGFT-treated patients versus 3.9 for sham-treated patients. The mean change in central retinal thickness was -413.0 μm for VEGFT-treated patients versus -381.8 μm for sham-treated patients. The percentage of patients with ocular neovascularization at week 24 was 0% for VEGFT-treated and 6.8% for sham-treated patients, respectively; at week 52 after receiving VEGFT PRN the percentages were 0% and 6.8% for VEGFT-treated and sham-treated. At week 24, the mean change from baseline in VFQ-25 total score was 7.2 vs. 0.7 for the VEGFT-treated and sham-treated groups; at week 52, the scores were 7.5 vs. 5.1 for the VEGFT-treated and sham-treated groups.

[0115] This example confirms that monthly dosing with 2 mg intravitreal VEGFT injections resulted in a statistically significant improvement in visual acuity at week 24, which was maintained up to week 52 with PRN dosing compared to sham-PRN treatment. VEGFT was generally well tolerated and had a generally favorable safety profile. EXAMPLES

[0116] Medication Regimen Specific non-limiting examples of dosing regimens within the scope of the present invention are as follows:

[0117] VEGFT 2 mg (0.05 mL) administered by intravitreal injection once every 4 weeks (monthly)

[0118] VEGFT administered by intravitreal injection once every 4 weeks for the first 8 weeks 2 mg (0.5 mL) followed by 2 mg (0.05 mL) via one intravitreal injection every 8 weeks.

[0119] VEGFT administered by intravitreal injection once every 4 weeks for the first 8 weeks 2 mg (0.5 mL) followed by 2 mg (0.05 mL) via intravitreal injection on a less frequent basis based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0120] VEGFT administered by intravitreal injection once every 4 weeks for the first 8 weeks 2 mg (0.5 mL) followed by 2 mg (0.05 mL) via intravitreal injection administered when needed (PRN) based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0121] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 12 weeks, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks.

[0122] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 12 weeks, followed by 2 mg (0.05 mL) via intravitreal injection on a less frequent basis based on visual and / or anatomical outcomes (assessed by a physician or other qualified healthcare professional).

[0123] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 12 weeks, followed by 2 mg (0.05 mL) via intravitreal injection administered when needed (PRN) based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0124] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 16 weeks, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks.

[0125] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 16 weeks, followed by 2 mg (0.05 mL) via intravitreal injection on a less frequent basis based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0126] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 16 weeks, followed by 2 mg (0.05 mL) via intravitreal injection administered when needed (PRN) based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0127] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 20 weeks, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks.

[0128] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 20 weeks, followed by 2 mg (0.05 mL) via intravitreal injection on a less frequent basis based on visual and / or anatomical outcomes (assessed by a physician or other qualified healthcare professional).

[0129] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 20 weeks, followed by 2 mg (0.05 mL) via intravitreal injection administered when needed (PRN) based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0130] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 24 weeks, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks.

[0131] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 24 weeks, followed by 2 mg (0.05 mL) via intravitreal injection on a less frequent basis based on visual and / or anatomical outcomes (assessed by a physician or other qualified healthcare professional).

[0132] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 24 weeks, followed by 2 mg (0.05 mL) via intravitreal injection administered when needed (PRN) based on visual and / or anatomical outcomes.

[0133] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 28 weeks, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks.

[0134] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 28 weeks, followed by 2 mg (0.05 mL) via intravitreal injection on a less frequent basis based on visual and / or anatomical outcomes (assessed by a physician or other qualified healthcare professional).

[0135] VEGFT 2 mg (0.5 mL) administered by intravitreal injection once every 4 weeks for the first 28 weeks, followed by 2 mg (0.05 mL) via intravitreal injection administered when needed (PRN) based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0136] VEGFT 2 mg (0.05 mL) administered by intravitreal injection as a single initial dose, followed by additional doses administered when needed (PRN) based on visual and / or anatomical outcomes (assessed by a physician or other certified healthcare professional).

[0137] The above-mentioned dosage regimen variations are understood by those skilled in the art and are within the scope of the present invention.For example, the amount of VEGFT and / or the volume of the formulation administered to a patient may vary based on the characteristics of the patient, the severity of the disease and other diagnostic evaluations by a physician or other qualified medical practitioner.

[0138] Any of the above-mentioned dosing regimens can be used to treat, for example, age-related macular degeneration (e.g., wet AMD, exudative AMD, etc.), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO; e.g., macular edema secondary to CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV; e.g., myopic CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathies, etc. EXAMPLES

[0139] A Phase 3, Double-Blind, Randomized Study of the Efficacy and Safety of Intravitreal IAI in Patients With Moderate-to-Severe NPDR (PANORAMA)-24 and 52 Week Results This was a phase 3, double-blind, randomized study of the efficacy and safety of intravitreal (IVT) aflibercept (IAI) for the improvement of moderate to severe nonproliferative diabetic retinopathy (NPDR). These data relate to outcomes achieved after 24 and 52 weeks.

[0140] Eligible patients were enrolled in one of three treatment groups in a 1:1:1 randomization scheme and stratified based on the patient's Diabetic Retinopathy Severity Scale (DRSS) score (level 47 vs. level 53) (see Figures 5 and 6). Only one eye was selected as the control eye.

[0141] Test Design The primary endpoint of the study was the proportion of patients who achieved a ≥ 2-step improvement from baseline in the DRSS at week 24 in the 2Q8 and 2Q16 groups combined, and at week 52 in each group.

[0142] Patients will be evaluated for efficacy (best corrected visual acuity [BCVA] using the 4-meter Early Treatment Diabetic Retinopathy Study [ETDRS] protocol, spectral-domain optical coherence tomography [SD OCT] and fluorescein angiography [FA] / fundus photography [FP]) and for ocular and systemic safety (including ophthalmologic examinations, visual field testing and clinical laboratory assessments) out to 100 weeks.

[0143] Secondary endpoints were also examined at week 52 and were as follows: (1) Proportion of patients who developed a vision-threatening complication (VTC) due to diabetic retinopathy by week 52. Vision-threatening complications are defined as a composite outcome of PDR (including patients with vitreous hemorrhage or tractional retinal detachment thought to be due to PDR) and ASNV. ASNV is defined as neovascularization of the iris (at least 2 cumulative clock hours) and / or frank neovascularization of the iridocorneal angle. (2) The proportion of patients who developed CI DME by week 52. (3) Time to onset of vision-threatening complications through week 52. (4) Time to onset of CI DME (central DME) through week 52. (5) The proportion of patients who underwent panretinal photocoagulation (PRP) by week 52, including patients who underwent endolaser vitrectomy. (6) Area under the curve (AUC) for change in BCVA from baseline at week 52.

[0144] Exam Schedule Days -21 to -1: Screening visit (Visit 1) Day 1: Baseline Visit (Visit 2) Week 24: Primary endpoint (2Q8 and 2Q16 combined) (Visit 7) Week 52: Primary endpoint (2Q8 and 2Q16 separately) and all secondary endpoints (Visit 11) Week 100: End of study (Visit 18)

[0145] Exclusion Criteria: Patients who met any of the following criteria at either the screening visit or Day 1 were excluded from the study: (1) presence of central macula-threatening DME in the study eye (within 1,000 microns of the foveal center); (2) evidence of retinal neovascularization on clinical examination or FA (fluorescein angiography); (3) previous focal or grid laser photocoagulation (within the central 1,000 microns of the fovea) or previous PRP in the study eye; (4) previous systemic or IVT anti-VEGF treatment in the study eye; (5) Previous intraocular steroids in the study eye; previous peribulbar steroids in the study eye within 120 days prior to Day 1; (6) history of vitreoretinal surgery in the study eye; (7) intraocular pressure (IOP) ≥ 25 mM Hg in the study eye; (8) evidence of active infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye; (9) any endophthalmitis or infection in either eye within 3 months prior to the screening visit; (10) current ASNV, vitreous hemorrhage, or tractional retinal detachment seen at screening evaluation in the target eye; (11) insufficient quality of ocular tissue to obtain fundus and optical coherence tomography (OCT) images in the study eye; allergy to fluorescein that precludes the ability to perform fluorescein angiography; (12) hemoglobin A1c (HbA1c) >12%, or uncontrolled diabetes in the investigator's opinion if HbA1c was ≤12%; (13) Uncontrolled blood pressure (systolic >160mmHg or diastolic >95mmHg in sitting position) defined as (14) History of cerebrovascular accident or myocardial infarction within 180 days prior to Day 1; (15) history of renal failure, dialysis or kidney transplant; (16) Women who are breastfeeding or have a positive serum hCG / urine pregnancy test at the screening or baseline visit; (17) Any concurrent ocular condition in the study eye that, in the investigator's opinion, may increase risk to the patient beyond that expected from standard procedures for IVT injection or may otherwise interfere with the injection procedure or with the evaluation of efficacy or safety; (18) History of other diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings that contraindicate the use of the investigational product or that give reasonable suspicion of a disease or condition that may affect the interpretation of the results of the study or place the patient at high risk for procedural complications; (19) Participation as a patient in an interventional clinical trial within 12 weeks prior to Day 1 of the study; (20) Sexually active males who are not willing to use adequate contraception prior to the first dose / initiation of first treatment, during the study, and for at least 3 months after the final dose * or women of childbearing age ** Adequate contraceptive methods include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for at least two menstrual cycles prior to screening; intrauterine device; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly or diaphragm plus contraceptive sponge, foam, or jelly. * Contraception is not required for men with a confirmed vasectomy **Postmenopausal women must be amenorrhea for at least 12 months to exclude pregnancy from consideration. Pregnancy testing and contraception are not required for women with a confirmed hysterectomy or tubal ligation. (21) Patients on systemic anti-VEGF treatment (i.e., bevacizumab, ziv-aflibercept) for tumor treatment (if the patient requires systemic anti-VEGF treatment during the study, the patient will be withdrawn).

[0146] Treatment Regimen: The three treatment groups have the following dosing regimens scheduled from Day 1 through Week 48:

[0147] 2Q8: aflibercept 2 mg Q8 through week 48 (after 5 initial monthly doses), followed by a flexible treatment regimen with aflibercept 2 mg from week 52 onwards;

[0148] 2Q16: aflibercept 2mg Q16 through week 96 (after 3 initial monthly doses and 1 Q8 interval);

[0149] Sham: Sham injections every 4 weeks (Q4) until week 16 followed by sham injections Q8 until week 96.

[0150] The data herein refers to the 2Q16 dose group as "Group 1"; the 2Q8 dose group as "Group 2" and the Sham group as "Sham."

[0151] Please refer to Figures 3 and 4.

[0152] The number of injections each dose group received after 24 weeks is shown in FIG. 7, and the number of injections after 52 weeks is shown in FIG.

[0153] To maintain masking, sham injections will be administered at treatment visits where patients do not receive active injections up to Week 96 for the 2Q8 and 2Q16 groups, and at all treatment visits for the sham group from baseline through Week 96. Masking will be maintained until the end of the study (Week 100).

[0154] Rescue procedure in study eye: Patients who develop PDR, ASNV, or centrally involved DME (CI DME) in the study eye will be treated if deemed appropriate by a masked physician. For any of these complications, FP will be performed before rescue procedures are performed.

[0155] Patients who develop CI DME will receive IVT aflibercept or laser photocoagulation and will no longer receive their randomized treatment. Rescue treatment will be performed by a masked or unmasked physician.

[0156] Patients who develop PDR and / or ASNV will undergo PRP or endolaser vitrectomy as appropriate, but will remain on their randomized treatment schedule. Panretinal photocoagulation or surgical intervention will be performed by either a masked or unmasked physician. In addition, they will receive one injection of aflibercept, which must be administered by an unmasked physician.

[0157] If treatment for DME, ASNV, or PDR occurs, patient data will be censored at the time of treatment for the primary analysis.

[0158] Study population 402 patients were enrolled. The patient population included men or women with type 1 or 2 diabetes, moderate to severe NPDR (without central macula-threatening DME), and in whom PRP could be safely deferred for at least 6 months. See Figures 5 and 6. Approximately 75% of patients had a DRSS of 47 and approximately 25% had a DRSS of 53.

[0159] For subjects who met the eligibility criteria in both eyes, the eye with the more severe DRSS score was selected as the study eye. If both eyes had equal scores, factors such as ocular dominance and patient priority were considered in making the selection.

[0160] Ocular Procedures (Efficacy and Safety) Best corrected visual acuity (BCVA): Visual function of the study eye and fellow eye will be assessed using the ETDRS protocol (The Early Treatment Diabetic Retinopathy Study Group 1985) at 4 meters at each study visit. Visual acuity testers are certified to ensure consistent measurements of BCVA. VA testers remain masked to treatment assignment. Best corrected visual acuity will be performed before any other ocular procedures are performed.

[0161] Intraocular Pressure (IOP): Intraocular pressure in the study eye is measured at every visit using Goldmann applanation tonometry or a Tono pen™. The same method of IOP measurement was used for each study patient throughout the study. Intraocular pressure is measured by a masked physician (or designee) prior to dosing (both eyes) and by an unmasked physician (or designee) approximately 30 minutes after dosing (study eye).

[0162] Slit Lamp Examination: Patients' anterior ocular structures and ocular adnexa will be examined bilaterally by a masked investigator using a slit lamp prior to dosing at each study visit.

[0163] Gonioscopy: Patients are evaluated by gonioscopy combined with slit-lamp biomicroscopy for the development of neovascularization of the iridocorneal angle. Examination is performed in the study eye only before application of mydriatic agents or if frank rubeosis is present.

[0164] Indirect Ophthalmoscopy: Patients' posterior pole and peripheral retina will be examined by indirect ophthalmoscopy at each study visit by a masked investigator pre-dosing (both eyes) and by an unmasked investigator post-dosing (study eye). Post-dosing evaluations will be performed immediately after injection (active or sham).

[0165] Fundus photography (FP) / fluorescein angiography (FA): The anatomy of the retinal vasculature and DRSS levels are evaluated by FA and FP.

[0166] Spectral Domain Optical Coherence Tomography (SD-OCT): Retinal characteristics are assessed at each visit using SD-OCT. Images are recorded and transmitted for both eyes. Images are sent to an independent reading center where they are read by masked readers. All OCT are electronically archived at the study site as part of the source documentation. Optical coherence tomography technicians are certified by the reading center to ensure consistency and quality in image collection. Every effort is made to ensure that study site OCT technicians remain masked to treatment allocation.

[0167] Visual Field Testing: Visual field testing will be assessed in the study eye using a Humphrey Visual Field Analyzer by a facility with access to this equipment. Technicians will be certified to ensure consistency and quality of the testing procedure. Every effort will be made to ensure that the study site visual field technicians remain masked to treatment assignment.

[0168] Adverse Events (AEs) Overall safety will be assessed by evaluation of treatment-emergent adverse events (TEAEs), physical examination, electrocardiogram (ECG), vital signs, and clinical safety laboratory tests (hematology, blood chemistry, hemoglobin A1c [HbA1c], and urinalysis) at various time points.

[0169] A TEAE is defined as an event (or a worsening of a pre-existing event during the treatment period) observed or reported after the first dose of study medication and before 30 days after the last dose of study medication (active or sham injection).

[0170] The investigator (or designer) will record all AEs occurring from the time the informed consent is signed until the end of the study. All serious adverse events (SAEs) must be reported within 24 hours regardless of the assessment of a causal relationship to the study drug.

[0171] Other events that must be reported within 24 hours include symptomatic overdosage of study drug (accidental or intentional overdosage of at least twice the intended dose of study drug within the intended therapeutic range, if associated with an AE) and pregnancy.

[0172] The severity of AEs is graded according to the following scale:

[0173] Mild: Does not significantly interfere with the patient's normal level of functioning. May be bothersome. Prescription medication is not usually necessary for symptom relief, but may be given depending on the patient's personality.

[0174] Moderate: Causes some impairment of function but is not harmful to health. Is unpleasant or embarrassing. Symptom treatment may be required.

[0175] Severe: causing significant impairment or dysfunction, clearly detrimental to the patient's health. Symptomatic treatment may be given and / or the patient is hospitalized.

[0176] Results and Conclusions The proportion of patients with > 2-step improvement in DRSS was significantly greater in the IAI group versus Sham. See Figures 8, 19, 21 and 22. Patients also achieved > 3-step improvement in the IAI group versus Sham. See Figures 9 and 32.

[0177] IAI reduced the number of patients who developed VTC and CI-DME. The proportion of patients who experienced VTC and / or DME at 24 and 52 weeks is outlined in Figures 10 and 23. Kaplan-Meier analysis of the probability of developing VTC or CI-DME over time in patients in each treatment group is described in Figures 24 and 25. Vision-threatening complications (VTC) are the progression to proliferative diabetic retinopathy (PDR) and anterior segment neovascularization (ASNV).

[0178] The changes in best corrected visual acuity (BCVA) experienced by patients in each treatment group at 24 and 52 weeks are summarized in Figures 11 and 26. The changes in central retinal thickness for each treatment group are summarized in Figures 12 and 27.

[0179] Efficacy outcomes were similar in the 2Q16 (arm 1) and 2Q8 (arm 2) groups.

[0180] Ocular treatment-emergent adverse events (TEAEs) at 24 and 52 weeks (Figures 13 and 28, respectively), ocular serious TEAEs at 24 and 52 weeks (Figures 14 and 29, respectively), intraocular inflammation at 24 and 52 weeks (Figures 15 and 30, respectively), and Antiplatelet Clinical Trials Collaboration (APTC) events at 24 and 52 weeks (Figures 16 and 31, respectively), as well as deaths at 24 weeks (Figure 17) are presented. At 52 weeks, there were a total of seven deaths (seven in the sham-treated group and one in the q8w-treated group). (APTC:Antithrombotic Trialists' Collaboration. Collaborative overview of randomized trial of antiplatelet therapy - II: Maintenance of vascular graft or arterial patency by antiplatelet therapy.Br Med J 1994;308:168~171; and Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002;324:71~86).

[0181] array SEQ ID NO:1 (DNA sequence having 1377 nucleotides): ATGGTCAGCTACTGGGACACCGGGGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGCTTCTCACAGGATCTAGTTCCGGAAGTGATACCGGTAGACCTTTCGTAGAGATGTACAGTGAAATCCCCGAAATTATACACATGACTGAAGGAAGGGAGCTCGTCATTCCCTGCCGGGTTACGTCACCTAACATCACTGTTACTTTAAAAAAGTTTCCACTTGACACTTTGATCCCTGATGGAAAACGCATAATCTGGGACAGTAGAAAGGGCTTCATCATATCAAATGCAACGTACAAAGAAATAGGGCTTCTGACCTGTGAAGCAACAGTCAATGGGCATTTGTATAAGACAAACTATCTCACACATCGACAAACCAATACAATCATAGATGTGGTTCTGAGTCCGTCTCATGGAATTGAACTATCTGTTGGAGAAAAGCTTGTCTTAAATTGTACAGCAAGAACTGAACTAAATGTGGGGATTGACTTCAACTGGGAATACCCTTCTTCGAAGCATCAGCATAAGAAACTTGTAAACCGAGACCTAAAAACCCAGTCTGGGAGTGAGATGAAGAAATTTTTGAGCACCTTAACTATAGATGGTGTAACCCGGAGTGACCAAGGATTGTACACCTGTGCAGCATCCAGTGGGCTGATGACCAAGAAGAACAGCACATTTGTCAGGGTCCATGAAAAGGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG AGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGTGTCAGCGTCCTCACCGTCCTGACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTG ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGCTCCTTCTTCCTTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA

[0182] sequence number 2 (polypeptide sequence with 458 amino acids): MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLY KTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVH EKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0183] The present invention is not limited in scope by the specific embodiments described herein, and indeed various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be within the scope of the appended claims.

Claims

1. 1. A method for treating or preventing diabetic retinopathy in a patient in need thereof, comprising administering to an eye of the patient: Approximately 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule; (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) The method comprises administering 3 or 5 monthly doses, followed by one or more secondary doses every 8 weeks, optionally in combination with further therapeutic agents or procedures.

2. VEGF antagonists include (i) comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) The method of claim 1, which is conbercept.

3. 3. The method of claim 1 or 2, wherein the patient is administered the VEGF antagonist by intravitreal injection.

4. The method of any one of claims 1 to 3, wherein the patient is administered 3 or 5 monthly doses, followed by one or more doses every 8 weeks.

5. 4. The method of any one of claims 1 to 3, wherein the patient receives three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose starting 8 weeks (at week 16) after the third monthly dose.

6. The method of any one of claims 1 to 3, wherein the patient receives one dose every 8 weeks.

7. The method of any one of claims 1 to 6, wherein the patient is suffering from non-proliferative diabetic retinopathy.

8. The method of any one of claims 1 to 6, wherein the patient is suffering from moderate or severe non-proliferative diabetic retinopathy.

9. The method of any one of claims 1 to 8, wherein the patient is afflicted with non-proliferative diabetic retinopathy characterized by a Diabetic Retinopathy Severity Scale level of 47 or 53.

10. The method of any one of claims 1 to 9, wherein the patient does not have diabetic macular edema or central-containing diabetic macular edema.

11. The method of any one of claims 1 to 10, wherein the patient has a baseline best corrected visual acuity (BCVA) ETDRS letter score of 69 or greater.

12. The method of any one of claims 1 to 11, wherein the patient's visual acuity is characterized by a Snellen visual acuity of 20 / 40 or better.

13. The method of any one of claims 1 to 12, wherein the patient is a human.

14. The method of any one of claims 1 to 13, wherein the patient is a human aged 18 years or older.

15. Patients: ・Retinal neovascularization; ・Anterior segment neovascularization (ASNV); vitreous hemorrhage; and / or Traction retinal detachment The method according to any one of claims 1 to 14, wherein the patient is not suffering from any of the following:

16. 1. A method for treating or preventing proliferative diabetic retinopathy in a patient in need of treatment, comprising administering to an eye of the patient: Approximately 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule; (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) The method comprises administering 3 or 5 monthly doses, followed by one or more secondary doses every 8 weeks, optionally in combination with further therapeutic agents or procedures.

17. VEGF antagonists include (i) comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) The method of claim 16, which is conbercept.

18. 18. The method according to claim 16 or 17 for preventing proliferative diabetic retinopathy.

19. 1. A method for preventing the progression of non-proliferative diabetic retinopathy to proliferative diabetic retinopathy, anterior segment neovascularization, diabetic macular edema and / or central-containing diabetic macular edema, comprising administering to an eye of the patient a vitreous ocular sclera comprising: Approximately 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule; (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) The method comprises administering 3 or 5 monthly doses, followed by one or more secondary doses every 8 weeks, optionally in combination with further therapeutic agents or procedures.

20. 20. The method of claim 19, wherein the non-proliferative diabetic retinopathy is characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of about 47 or 53.

21. A method for causing a reduction or preventing an increase in the Diabetic Retinopathy Severity Scale (DRSS) level of non-proliferative diabetic retinopathy (NPDR) in a patient, comprising administering to the patient's eye Approximately 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule; (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) The method comprises administering 3 or 5 monthly doses, followed by one or more secondary doses every 8 weeks, optionally in combination with further therapeutic agents or procedures.

22. VEGF antagonists include (i) comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) The method of claim 21, which is conbercept.

23. 23. The method of claim 21 or 22 for effecting a reduction, wherein the reduction is by at least two levels.

24. 23. The method of claim 21 or 22 for effecting a reduction, wherein the reduction is to at least three levels.

25. The method of any one of claims 16 to 24, wherein the patient has NPDR without diabetic macular edema.

26. The method of any one of claims 16 to 25, wherein the patient has NPDR without central-involving diabetic macular edema.

27. Patients: (i) having diabetes; (ii) having a hemoglobin A1c of about 8.5; (iii) having an ETDRA BCVA score of about 82; (iv) have a central retinal thickness of about 247 μm; (v) having a Diabetic Retinopathy Severity Score of 47 or 53; and / or (viii) age of about 56 years.

28. 28. The method of any one of claims 16 to 27, wherein the patient receives about 3 to about 5 injections over a 24 week period.

29. The method of any one of claims 16 to 28, wherein the patient is administered the VEGF antagonist for at least 24 weeks.

30. The patient is administered a VEGF antagonist for at least 24 weeks: (i) at least a two-step improvement from baseline in Diabetic Retinopathy Severity Scale (DRSS) score; (ii) at least a 3-step improvement from baseline in Diabetic Retinopathy Severity Scale (DRSS) score; (iii) an improvement in best corrected visual acuity of at least about 1.9 letters; (iv) does not experience a reduction in best-corrected visual acuity of more than 4 letters; (v) not developing diabetic macular edema; (vi) not develop centrally involved diabetic macular edema; (vii) not experiencing any sight-threatening complications; (viii) does not develop proliferative diabetic retinopathy; (ix) does not develop anterior segment neovascularization; and / or (x) experience a reduction in central retinal thickness of about 19 μm; The method according to any one of claims 16 to 29, further comprising achieving one or more of the following:

31. A method for treating or preventing the onset or recurrence of vision-threatening complications or blindness, maintaining or improving vision, and / or maintaining or reducing central retinal thickness in an eye of a subject with diabetic retinopathy, comprising administering to the patient's eye Approximately 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule; (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) The method comprises administering 3 or 5 monthly doses, followed by one or more secondary doses every 8 weeks, optionally in combination with further therapeutic agents or procedures.

32. 32. The method of claim 31, wherein the subject has non-proliferative diabetic retinopathy.

33. 32. The method of claim 31, wherein the subject has moderate to severe non-proliferative diabetic retinopathy.

34. In the other eye of the subject About 2 mg of the VEGF antagonist (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or 32. The method of claim 31, further comprising administering (ii) 3 or 5 monthly doses, followed by one or more secondary doses every 8 weeks.

35. VEGF antagonists include (i) comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) The method of claim 31, which is conbercept.

36. It is a package A drug container; and In the patient's eyes, Approximately 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule; (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 5 monthly doses followed by one or more secondary doses every 8 weeks; instructions for using the drug to treat or prevent diabetic retinopathy in a patient in need of treatment, showing the use of the drug by administering the drug of, optionally in conjunction with an additional therapeutic agent or procedure. The package comprising:

37. VEGF antagonists include (i) comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) The package of claim 36 which is conbercept.

38. The package of any one of claims 36 to 37, wherein the instructions indicate that the drug is administered by intravitreal injection.

39. 39. The package of any one of claims 36 to 38, wherein the instructions indicate that the drug is to be administered in 3 or 5 monthly doses, followed by one or more doses every 8 weeks.

40. 40. The package of any one of claims 36 to 39, wherein the instructions indicate that the drug is to be administered in three monthly doses, followed by one or more secondary doses every 16 weeks, with the first secondary dose starting 8 weeks after the third monthly dose (at week 16).

41. 39. The package of any one of claims 36 to 38, wherein the instructions indicate that the drug is to be administered in one dose every 8 weeks.

42. A package comprising: A drug container; and In the patient's eyes, Approximately 2 mg of a VEGF antagonist that is a VEGF receptor-based chimeric molecule; (i) three monthly doses followed by one or more secondary doses every 16 weeks, with the first secondary dose beginning 8 weeks (at week 16) after the third monthly dose; or (ii) 3 or 5 monthly doses followed by one or more secondary doses every 8 weeks; instructions for using the drug to treat or prevent proliferative diabetic retinopathy in a patient in need of treatment, showing the use of the drug by administering the drug of, optionally in conjunction with an additional therapeutic agent or procedure. The package comprising:

43. VEGF antagonists include (i) comprises (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO:2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO:2; (ii) comprises (1) immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and (2) Ig domain 3 of a second VEGF receptor, and (3) a multimerization component; (iii) aflibercept; or (iv) The package of claim 42 which is conbercept.

Images